KR20010083084A - Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake - Google Patents

Abstract

The present invention provides novel benzothiene, derivatives and analogs thereof; Methods of preparing these compounds; Pharmaceutical compositions containing these compounds; And methods of using these compounds and compositions in medicine, in particular in the manufacture of a medicament for the prevention and treatment of hyperlipidemic conditions, such as those associated with atherosclerosis or hypercholesterolemia in mammals.

Description

BENZOTHIEPINES HAVING ACTIVITY AS INHIBITORS OF ILEAL BILE ACID TRANSPORT AND TAUROCHOLATE UPTAKE}

It is well established that hyperlipidemic conditions associated with increased concentrations of total cholesterol and low density lipoprotein cholesterol are major risk factors for coronary heart disease and especially atherosclerosis. Interfering with the circulation of bile acids in the lumen of the intestine has been shown to decrease serum cholesterol levels in a causal relationship. There is an accumulation of epidemiologic data showing that such a reduction leads to an improvement in the disease state of atherosclerosis. Stedronsky, "Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties," Biochimica et Biophysica Acta , 1210 (1994) 255-287, discusses the biochemistry and physiology of known active agents, including bile acids and cholesterol. .

Pathophysiological changes are known to be consistent with the blockage of intrahepatic circulation of bile acids in humans [Heubi, JE et al., "Primary Bile Acid Malabsorption: Defective in Vitro Ileal Active Bile Acid Transport", Gastroenterology , 1982: 83: 804- 11].

Indeed, cholestyramine binds bile acids in the intestine and interferes with its normal intrahepatic circulation [Reihner, E. et al., "Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients ". Journal of Lipid Research , Volume 31, 1990, 2219-2226 and Sucking et al., "Cholesterol Lowering and bile acid excretion in the hamster with cholestyramine treatment", Atherosclerosis , 89 (1991) 183-190]. It not only increases cholesterol bile acid synthesis by the liver using cholesterol, but also upregulates liver LDL receptors that increase the clearance of cholesterol and decrease serum LDL cholesterol levels.

In another study on the reduction of bile acid recycling, the ileal bile acid transport system is an putative pharmaceutical target for the treatment of hypercholesterolemia based on the blockade of intrahepatic circulation by specific transport inhibitors [Kramer et al. Intestinal Bile Acid Absorption "The Journal of Biological Chemistry, Vol. 268, No. 24, Issue of August 25, pp. 18035-18046, 1993].

A series of patent applications, such as Canadian Patent Application No. 2,025,294; 2,078,588; 2,078,588; 2,085,782; And 2,085,830; And EP application 0 379 161; 0 549 967; 0 559 064; And 0 563 731 discloses Hoechst actigel gelshafts, including bile acids, are polymers and derivatives of various naturally occurring components of the intestinal circulatory system, which aim to reduce LDL cholesterol levels sufficiently effective as a medicament. Inhibits physiological bile acids, especially for use as hypocholesterolemia agents.

Inhibition of bile acid transport in vitro is disclosed to exhibit hypotensive activity in international patent application WO93 / 16055 (named "Hypolipidemic Benzothiazepine compounds", Applicant: Welcome Foundation Limited).

Selected benzothiepines are disclosed in a number of uses in international patent application WO93 / 321146, including fatty acid metabolism and coronary vascular disease.

Other selected benzothiepines are known to be used for hypolipidemia and hypocholesterolemia, and are disclosed in patent applications EP 508425, FR 2661676 and WO92 / 18462, particularly for the treatment or prevention of atherosclerosis. Each is limited by an amide bound to a carbon adjacent to the phenyl ring of the fused bicyclo benzothiene ring.

The above references represent a continuing effort to explore safe and effective formulations for the prevention and treatment of hypolipidemia and their usefulness as hypocholesterolemia agents.

Further selected benzothiepines are disclosed for use in various disease states, but not within the scope of use of the present invention. Examples thereof include EP 568 898A (summarized to DerwentAbstract No. 93-351589); WO89 / 1477 / A, summarized as Derwent Abstract No. 89-370688; U.S. 3,520,891, summarized as Derwent Abstract No. 50701R-B; US 3,287,370, US 3,389,144, US 3,694,446 (summarized to Derwent Abstract No. 65860T-B) and WO 92/18462.

The present invention adds its efforts by providing novel benzothiepines, pharmaceutical compositions and methods of using the same.

The present invention uses novel benzothiepines, derivatives and analogs thereof, pharmaceutical compositions containing them, and their use in medicine, particularly in the prevention and treatment of hyperlipidemic conditions such as those associated with atherosclerosis or hypercholesterolemia in mammals. It is about use.

Accordingly, in its various aspects the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof:

In the above formula,

q is an integer from 1 to 4;

n is an integer from 0 to 2;

R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from;

Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ ,

Alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ⁺ R ^{9 a -, P + R 9 R} 10 a - , or may have one or more carbon is replaced by a phenylene,

R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or

R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl;

R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above;

R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² ,

Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or

R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring;

R ⁵ and R ⁶ are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ⁹ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from

Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be,

Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkoxyalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide,

R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl pyridinyl, carboxyalkyl heterocyclyl ^{thio, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO ₃ R ^9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A - May be substituted with one or more groups selected from the group consisting of S ⁺ R ⁹ R ¹⁰ A ^- and C (O) OM,

Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl;

At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate,

Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a

Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

Acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, 4 is a heterocycle, and 4-heteroaryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR 9, S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶ ) may be substituted with one or more substituents selected from the group consisting of OR ¹⁷ and C (O) OM,

Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ;

The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 There may be substituted with one or more groups selected from the group consisting ^{of, -, S + R 13 R} 14 a - , and ^{N + R 9 R 11 R 12} a

Provided that both R ⁵ and R ⁶ may not be hydrogen, OH or SH, and when R ⁵ is OH, R ¹ , R ² , R ³ , R ⁴ , R ⁷ and R ⁸ may not all be hydrogen; ;

Provided that when R ⁵ or R ⁶ is phenyl, then only one of R ¹ or R ² is H;

With the proviso that when q = 1 and R ^x is styryl, anilido or anilinocarbonyl, then only one of R ⁵ or R ⁶ is alkyl;

Provided that when n is 1, R ¹ , R ³ , R ⁷ and R ⁸ are hydrogen, R ² is hydrogen, alkyl or aryl and R ⁴ is amino or unsubstituted substituted with one or more alkyl or aryl radicals Amino, R ⁵ is hydrogen, alkyl or aryl, and R ⁶ is not hydroxy.

Preferably R ⁵ and R ⁶ may be independently selected from the group consisting of H, aryl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl,

Wherein the aryl, heteroaryl, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR ¹³ SO ₂ R ¹⁴ , NR ¹³ SONR ¹⁴ R ¹⁵ , NR ¹³ SO ₂ NR ¹⁴ R to ^{- 15, P (O) R} 13 R 14, P + R 13 R 14 R 15 a -, P (OR 13) OR 14, S + R 13 R 14 a - , and ^{N + R 9 R 11 R 12} a May be substituted with one or more substituents independently selected from the group consisting of,

Wherein alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7,} P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene,

Wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO ₃ R ^7, CO ₂ R ^7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a -, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, arylalkyl, tetravalent hetero Cycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ A ^- and P (O) (OR ⁷ ) OR ⁸ which may be further substituted with one or more substituents selected from the group .

More preferably R ⁵ or R ⁶ is represented by the formula -Ar- (R ^y ) _t ,

Wherein t is an integer from 0 to 5;

Ar is phenyl, thiophenyl, pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl, anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl, imidazolyl, pyrazolyl, Oxazolyl, isoxazolyl, pyrimidinyl, thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzoisothiazolyl;

One or more R ^y is independently alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O ) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR ¹³ SO ₂ R ¹⁴ , NR ¹³ SONR ¹⁴ R ¹⁵ , NR ¹³ SO ₂ NR ¹⁴ R ¹⁵ , P (O) R ¹³ R ¹⁴ , ^{P + R 13 R 14 R 15} a -, P (OR 13) OR 14, S + R 13 R 14 a - , and ^{N + R 9 R 11 R 12} a - a is independently selected from the group consisting of,

Wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO ₃ R ^7, CO ₂ R ^7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 A -, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, Further substituted with one or more substituents selected from the group consisting of a tetravalent heterocycle, a tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ A ^- and P (O) (OR ⁷ ) OR ⁸ Can be,

Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene.

More preferably R ⁵ or R ⁶ is represented by the formula II:

The first class of compounds of particular interest consists of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, having the following group definitions:

q is 1 or 2;

n is 2;

R ¹ and R ² are each alkyl;

R ³ is hydroxy;

R ⁴ and R ⁶ are hydrogen;

R ⁵ is represented by Formula II:

[Formula II]

In the above formula,

t is an integer from 0 to 5;

At least one R ^y is OR ¹³ ;

R ¹³ is hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, alkylarylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, tetravalent heteroaryl and tetravalent heteroarylalkyl Selected from the group consisting of;

It said R ¹³ alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups are ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9 ^{, P + R 9 R 10 a} -, P (O) R 9, phenylene, carbohydrate, amino optionally having one or more carbon is replaced by a peptide or polypeptide, and;

R ¹³ is a sulfoalkyl, tetravalent heterocyclic, 4 ^{heteroaryl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO ₃ R ^9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A - May be substituted with one or more groups selected from the group consisting of S ⁺ R ⁹ R ¹⁰ A ^- and C (O) OM,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

R ⁹ and R ¹⁰ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl and alkylammoniumalkyl;

R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or

R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring;

R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M;

R ⁷ and R ⁸ are hydrogen;

At least one R ^x is independently selected from the group consisting of alkoxy, alkylamino and dialkylamino.

A second class of compounds of particular interest consists of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, having the following group definitions:

q is an integer from 1 to 4;

n is an integer from 0 to 2;

R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from

Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ ,

Alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ⁺ R ⁹ May have one or more carbons replaced by A ⁻ , P ⁺ R ⁹ R ¹⁰ A ⁻ or phenylene,

R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or

R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl;

R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above;

R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² ,

Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or

R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring;

R ⁵ is aryl substituted with one or more OR ^13a ,

Wherein R ^13a is in the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl Selected,

R ^13a is hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, sphere No ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN , _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 A - , and C (O May be substituted with one or more groups selected from the group consisting of OM,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M;

R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military,

Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be,

Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide,

R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM,

Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl;

R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl;

At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate,

Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a

Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

Acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, 4 is a heterocycle, and 4-heteroaryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR 9, S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶ ) may be substituted with one or more substituents selected from the group consisting of OR ¹⁷ and C (O) OM,

Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ;

The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a.

Preferred compounds of this class are

R ⁵ is phenyl substituted with OR ^13a ;

R ^13a is independently selected from the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl and carboxyalkylaminocarbonylalkyl;

R ^13a is a compound that may be substituted with one or more groups selected from the group consisting of carboxy, tetravalent heterocycle, tetravalent heteroaryl, and NR ⁹ R ¹⁰ .

More preferred compounds of this class are

R ⁵ is phenyl substituted with OR ^13a ;

R ^13a is alkylarylalkyl;

R ^13a is a compound that may be substituted with one or more groups selected from the group consisting of a tetravalent heterocycle and a tetravalent heteroaryl.

More preferred compounds of this class are

R ⁵ is phenyl substituted with OR ^13a ;

R ^13a is alkylphenylalkyl;

R ^13a is a compound that may be substituted with one or more groups selected from the group consisting of a tetravalent heterocycle and a tetravalent heteroaryl.

A third class of compounds of particular interest consists of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, having the following group definitions:

q is an integer from 1 to 4;

n is an integer from 0 to 2;

R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from

Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ ,

Wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ^{+ R 9 a -, P + R} 9 R 10 a - , or may have one or more carbon is replaced by a phenylene,

R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or

R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl;

R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above;

R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² ,

Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or

R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring;

R ⁵ is aryl substituted with one or more OR ^13b ,

Wherein R ^13b is alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent Heterocycle, tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

R ^13b is substituted with one or more groups selected from the group consisting of carboxyalkyl, heterocycle, heteroaryl, heteroaryl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl or guanidinyl,

R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military,

Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be,

Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide,

R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM,

Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring;

R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl;

At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate,

Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a

Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

Here, acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, tetravalent hetero heterocycle and 4 aryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ Or may be substituted with one or more substituents selected from the group consisting of PO (OR ¹⁶ ) OR ¹⁷ and C (O) OM,

Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ;

The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a.

Preferred compounds of this class are

R ⁵ is phenyl substituted with OR ^13b ;

R ^13b is independently selected from the group consisting of alkyl, tetravalent heteroarylalkyl tetravalent heterocyclylalkyl;

R ^13b is a compound which may be substituted by one or more groups selected from the group consisting of heterocycle, heteroaryl and guanidinyl.

A fourth class of compounds of particular interest consists of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof having the following group definitions:

q is an integer from 1 to 4;

n is an integer from 0 to 2;

R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from

Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ ,

Wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ^{+ R 9 a -, P + R} 9 R 10 a - , or may have one or more carbon is replaced by a phenylene,

R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or

R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl;

R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above;

R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² ,

Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or

R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring;

R ⁵ is aryl substituted with one or more OR ^13b ,

Wherein R ^13b is alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent Heterocycle, tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkoxyalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

R ^13b is ^{OR 9a, NR 9a R 10,} N + R 9a R 11 R 12 A -, SR 9a, S (O) R 9a, SO 2 R 9a, SO 3 R 9a, CO 2 R 9a, CONR 9a R ¹⁰ , SO ₂ NR ^9a R ¹⁰ , P ⁺ R ^9a R ¹⁰ R ¹¹ A ^- and S ⁺ R ^9a R ¹⁰ A ^-and are substituted with one or more groups selected from the group consisting of

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

Wherein R ^9a is selected from the group consisting of carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino and carboxyalkylaminoalkyl;

R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military,

Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be,

Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkoxyalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide,

R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM,

Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring;

R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl;

At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate,

Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a

Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

Here, acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, tetravalent hetero heterocycle and 4 aryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ May be substituted with one or more substituents selected from the group consisting of PO (OR ¹⁶ ) OR ¹⁷ and C (O) OM,

Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ;

The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a.

Preferred compounds of this class are

R ⁵ is phenyl substituted with OR ^13b ;

R ^13b is independently selected from the group consisting of alkyl and alkoxyalkyl;

R ^13b may be substituted with one or more groups selected from the group consisting of OR ^9a and NR ^9a R ¹⁰ ;

R ^9a is selected from the group consisting of carboxyalkyl, carboxyheteroaryl and carboxyheterocycle;

R ¹⁰ is a compound that is carboxyalkyl.

A fifth class of compounds of particular interest consists of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof, having the following group definitions:

q is an integer from 1 to 4;

n is an integer from 0 to 2;

R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from

Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ ,

Wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ^{+ R 9 a -, P + R} 9 R 10 a - , or may have one or more carbon is replaced by a phenylene,

R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or

R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl;

R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above;

R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² ,

Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or

R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring;

R ⁵ is aryl substituted with one or more OR ^13b ,

Wherein R ^13b is alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent Heterocycle, tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

R ^13b is carboxyalkyl ^{heterocyclyl, NR 9 R 10a, CONR 9} R 10a, SO 2 NR 9 R 10a, P + R 9 R 10a R 11 A - selected from the group consisting of ^- and S ⁺ R ⁹ R ^10a A Substituted with one or more groups,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

Wherein R ^10a is selected from the group consisting of carboxyalkyl, carboalkoxyalkyl, carboxylalkylamino, heteroarylalkyl and heterocyclylalkyl;

R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military,

Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be,

Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide,

R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM,

Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring;

R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl;

At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate,

Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a

Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

Here, acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, tetravalent hetero heterocycle and 4 aryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ May be substituted with one or more substituents selected from the group consisting of PO (OR ¹⁶ ) OR ¹⁷ and C (O) OM,

Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ;

The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a.

Preferred compounds of this class are

R ⁵ is phenyl substituted with OR ^13b ;

R ^13b is alkyl;

R ^13b is substituted with NR ⁹ R ^10a ;

R ⁹ is hydrogen;

R ¹⁰ is a compound that is heteroarylalkyl.

A sixth class of compounds of particular interest consists of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof, having the following group definitions:

q is an integer from 1 to 4;

n is an integer from 0 to 2;

R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from

Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ ,

Wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ^{+ R 9 a -, P + R} 9 R 10 a - , or may have one or more carbon is replaced by a phenylene,

R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or

R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl;

R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above;

R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² ,

Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or

R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring;

R ⁵ is NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR ¹³ SO ₂ R ¹⁴ , NR ¹³ SONR ¹⁴ R ¹⁵ and NR ¹³ SO ₂ NR ¹⁴ R ¹⁵ is aryl substituted with one or more substituents independently selected from the group consisting of:

Wherein R ¹³ , R ¹⁴ and R ¹⁵ are hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, Consisting of heterocycle, heteroaryl, tetravalent heterocycle, tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl Selected from the military,

R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring;

R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military,

Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of,

Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation,

The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be,

Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl,

Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide,

R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM,

Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or

R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or

R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring;

R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl;

R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl;

At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate,

Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a

Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,

Here, acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, tetravalent hetero heterocycle and 4 aryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ May be substituted with one or more substituents selected from the group consisting of PO (OR ¹⁶ ) OR ¹⁷ and C (O) OM,

Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,

Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ;

The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a.

Preferred compounds of this class are

R ⁵ is aryl substituted with a radical selected from the group consisting of NR ¹³ C (O) NR ¹⁴ R ¹⁵ and NR ¹³ CO ₂ R ¹⁴ .

More preferred compounds of this class are

R ⁵ is phenyl substituted with a radical selected from the group consisting of NR ¹³ C (O) NR ¹⁴ R ¹⁵ and NR ¹³ CO ₂ R ¹⁴ .

Other aspects of the invention relate to compounds of formula (I), including each of the foregoing embodiments, wherein one or more of the following conditions (1) to (6) are present:

(1) R ¹ and R ² are independently selected from the group consisting of hydrogen and alkyl. R ¹ and R ² are preferably independently selected from the group consisting of C _1-6 alkyl. More preferably R ¹ and R ² are equally C _1-6 alkyl. More preferably R ¹ and R ² are butyl; / or

(2) R ³ and R ⁴ are independently selected from the group consisting of hydrogen and OR ⁹ , wherein R ⁹ is defined as set forth above. It is preferable that R ³ is hydrogen and R ⁴ is OR ⁹ . More preferably R ³ is hydrogen and R ⁴ is hydroxy

(3) R ⁵ is substituted aryl. It is preferred that R ⁵ is substituted phenyl. R ⁵ is OR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR More preferably aryl substituted with one or more substituents independently selected from the group consisting of ¹³ SOR ¹⁴ , NR ¹³ SO ₂ R ¹⁴ , NR ¹³ SONR ¹⁴ R ¹⁵ and NR ¹³ SO ₂ NR ¹⁴ R ¹⁵ , wherein R is ¹³ , R ¹⁴ and R ¹⁵ are as set forth above. More preferably R ⁵ is phenyl substituted with OR ¹³ . Even more preferred are phenyl in which R ⁵ is substituted with OR ¹³ in the para or meta position, wherein R ¹³ is a tetravalent heterocycle, tetravalent heteroaryl or substituted amino

(4) R ⁶ is hydrogen and / or

(5) R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl. R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and C _1-6 alkyl. R ⁷ and R ⁸ are preferably hydrogen

(6) R ^x is selected from the group consisting of OR ¹³ and NR ¹³ R ¹⁴ . It is preferred that R ^x is selected from the group consisting of alkoxy, amino, alkylamino and dialkylamino. More preferably R ^x is selected from the group consisting of methoxy and dimethylamino.

The invention also relates to a compound selected from compounds of the formulas DI, DII and DIII:

R ²⁰ ━R ¹⁹ ━R ²¹

In the above formulas,

R ¹⁹ is selected from the group consisting of alkanediyl, alkenediyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrates, amino acids, peptides and polypeptides, wherein alkane diyl, alkenediyl, alkyne Diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrates, amino acids, peptides and polypeptides are O, NR ⁷ , N ⁺ R ⁷ R ⁸ , S, SO, SO ₂ , S ⁺ R ⁷ R ⁸ , PR ⁷ , P ⁺ R ⁷ R ⁸ , phenylene, heterocycle, tetravalent heterocycle, tetravalent heteroaryl or aryl may have one or more carbon atoms,

Alkanes Diyl, Alkenes Diyl, Alkynes Diyl, Polyalkanes Diyl, Alkoxy Diyl, Polyether Diyl, Polyalkoxy Diyl, Carbohydrates, Amino Acids, Peptides and Polypeptides are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl , Cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , P (O) R ^{13 R 14, P + R 13} R 14 R 15 a -, P (OR 13) OR 14, S + R 13 R 14 a - , and ^{N + R 9 R 11 R 12} a - is independently selected from the group consisting of May be substituted with one or more substituents,

R ¹⁹ also includes functional linkages wherein R ¹⁹ is bonded to R ²⁰ , R ²¹ or R ²² in the compounds of Formulas DII and DIII and to R ²³ in the compound of Formula DIII. R ²⁰ , R ²¹ or R ²² and R ²³ each comprise a benzothiene moiety as described above which is therapeutically effective at inhibiting bile acid transport in the ileum.

The present invention also relates to a compound selected from compounds of the formulas DI, DII and DIII, in which each of R ²⁰ , R ²¹ , R ²² and R ²³ comprises a benzothiene moiety corresponding to the formula DIV or DIVA do:

In the above formula,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^x , q and n are as defined in Formula I above, and R ⁵⁵ is a covalent bond or arylene.

In the compounds of the formula DIV, it is particularly preferred that R ²⁰ , R ²¹ and R ²² respectively for the formulas DII and DIII and R ²³ for the formula DIII are bonded to R ¹⁹ at their 7- or 8-positions. In the compounds of the formula DIVA, it is particularly preferred that R ⁵⁵ comprises a phenylene moiety bonded to R ¹⁹ at m-carbon or p-carbon.

Examples of the formula DI include the following.

In either of the dimer or multimeric structures discussed above, the benzothiene compounds of the invention can be used alone or in various combinations.

In the case of any compound of the present invention, R ¹ and R ² may be ethyl / butyl or butyl / butyl.

Another class of such compounds include the following compounds:

In another aspect, the present invention provides a pharmaceutical composition for preventing or treating a disease or condition in which a bile acid transport inhibitor is prescribed, such as a hyperlipidemic condition such as atherosclerosis. Such compositions may comprise pharmaceutically acceptable carriers, excipients or diluents alone or in combination and any of the compounds disclosed above in an amount effective to reduce blood levels of bile acids or reduce their transport through the digestive system membranes. .

In another aspect, the invention also provides a method of treating a disease or condition in a mammal, including a human, in which a bile acid inhibitor is prescribed, which method, alone or in combination, in any unit dosage form or any of the compounds disclosed above Administering to the patient in need thereof an effective amount in a divided dosage form.

In a further aspect, the invention also provides a use for the manufacture of a medicament for use in treating a disease or condition in a mammal, including humans, in which bile acid transport inhibitors are prescribed, alone or in combination with any of the compounds disclosed above. to provide.

In another aspect, the present invention also provides a method of preparing a compound of the present invention as discussed in more detail below.

Further scope of the applicability of the present invention will become apparent from the detailed description given below. However, it should be understood that the following detailed description and implementations are presented for purposes of illustration only and illustrating preferred embodiments of the invention, for various modifications and variations within the spirit and scope of the invention. This is because it will be clear to those skilled in the art.

Detailed description of the invention

The following detailed description is presented to those skilled in the art in practicing the present invention. However, these detailed descriptions should not be construed as limiting the invention unnecessarily, as modifications and variations of the embodiments discussed herein can be made by those skilled in the art without departing from the scope or spirit of the invention.

References cited herein are hereby incorporated by reference in their entirety, including the contents of the references cited in these main references.

Justice

To help understand the detailed description below, the following definitions are given.

"Alkyl", "alkenyl" and "alkynyl", unless stated otherwise, in the present invention are straight or branched from 1 to 20 carbon atoms for alkyl or 2 to 20 carbon atoms for alkenyl and alkynyl Chain hydrocarbons and, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl, butenyl, pentenyl or hexenyl and ethynyl, propynyl, butynyl, pentynyl or hexynyl and That isomer means.

"Aryl" means a fully unsaturated mono ring or a multi-ring carbocyclic ring, such as, but not limited to, substituted or unsaturated phenyl, naphthyl or anthracenyl.

"Heterocycle" means a saturated or unsaturated mono or multi-ring carbocyclic ring in which one or more carbon atoms may be replaced by N, S, P or O. This includes, for example, the following structural formula:

In the above structural formula,

Z, Z ', Z "or Z"' is C, S, P, O or N, provided that one of Z, Z ', Z "or Z"' is other than carbon, but is further Z It is not O or S when attached to an atom or when attached to another O or S atom. It is also understood that any substituent is attached to Z, Z ', Z "or Z"' only when each is C.

The term "heteroaryl" refers to a fully unsaturated heterocycle.

Among the "heterocycles" or "heteroaryls", the point of attachment to the molecule may be at a heteroatom or at another position in the ring.

The term "tetravalent heterocycle" means a heterocycle having a plurality of bonds such that at least one of the heteroatoms, such as O, N, S or P, is positively charged. The point of attachment of the tetravalent heterocycle to the molecule may be at a hetero atom or elsewhere.

The term "tetravalent heteroaryl" means a heterocycle having a plurality of bonds such that at least one of the heteroatoms, such as O, N, S or P, is positively charged. The point of attachment of the tetravalent heterocycle to the molecule may be at a hetero atom or elsewhere.

The term "halogen" means a fluoro, chloro, bromo or iodo group.

The term "haloalkyl" refers to alkyl substituted with one or more halogens.

The term "cycloalkyl" refers to a monocyclic or polycyclic carbocyclic ring in which each ring has 3 to 10 carbon atoms and any ring may have one or more double or triple bonds. Radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl and cycloheptyl The term “cycloalkyl” means that the cycloalkyl ring has a carbon ring with a seven-membered heterocycle ring of benzothiene It includes a spiral system.

The term "diyl" refers to a diradical moiety, which has two attachment points to the molecule.

The term "oxo" means double bonded oxygen.

The term "polyalkyl" refers to a branched or straight chain hydrocarbon chain having a molecular weight of up to about 20,000, more preferably up to about 10,000, most preferably up to about 5,000.

The term "polyether" is a polyalkyl in which one or more carbons are replaced by oxygen, wherein the polyether has a molecular weight of up to about 20,000, more preferably up to about 10,000 and most preferably up to about 5,000.

The term "polyalkoxy" refers to a polymer of alkylene oxides, wherein the polyalkoxy has a molecular weight of at most about 20,000, more preferably at most about 10,000 and most preferably at most about 5,000.

The term "cycloalkylidene" refers to a monocyclic or polycyclic oxygen ring in which the carbon inside the ring structure is double bonded to an atom not belonging to the ring structure.

The term "carbohydrate" refers to monosaccharides, disaccharides, trisaccharides or polysaccharides, which can be up to about 20,000 in molecular weight, such as hydroxypropyl-methylcellulose or chitosan.

The term "peptide" refers to a polyamino acid having up to about 100 amino acid units.

The term "polypeptide" means a polyamino acid having about 100 to about 1000 amino acid units, more preferably about 100 to 750, and most preferably about 100 to about 500 amino acids.

The term " alkylammoniumalkyl " means an NH ₂ group or a mono substituted, di substituted or tri substituted amino group, any of which is bonded to alkyl, wherein the alkyl is bonded to the molecule.

The term "triazolyl" includes all positional isomers. In all other heterocycles and heteroaryls having at least one ring heteroatom and capable of isomers thereof, such isomers are included in the definitions of such heterocycles and heteroaryls.

The term "sulfo" refers to a sulfo group, -SO ₃ H or a salt thereof.

The term "sulfoalkyl" refers to an alkyl group to which a sulfonate group is bonded, which alkyl is bonded to the molecule.

The term "arylalkyl" refers to an aryl substituted alkyl radical such as benzyl. The term "alkylarylalkyl" means an arylalkyl radical substituted on an aryl group with one or more alkyl groups.

The term "heterocyclylalkyl" refers to an alkyl radical substituted with one or more heterocycle groups. Preferred heterocyclylalkyl radicals are "lower heterocyclylalkyl" radicals having one or more heterocycle groups attached to an alkyl radical having 1 to 10 carbon atoms.

The term "heteroarylalkyl" refers to alkyl radicals substituted with one or more heteroaryl groups. Preferred heteroarylalkyl radicals are "lower heteroarylalkyl" radicals having one or more heteroaryl groups attached to an alkyl radical having 1 to 10 carbon atoms.

The term "tetravalent heterocyclylalkyl" refers to an alkyl radical substituted with one or more tetravalent heterocycle groups. Preferred tetravalent heterocyclylalkyl radicals are "lower tetravalent heterocyclylalkyl" radicals having one or more tetravalent heterocycle groups attached to an alkyl radical having 1 to 10 carbon atoms.

The term "tetravalent heteroarylalkyl" means an alkyl radical substituted with one or more tetravalent heteroaryl groups. Preferred tetravalent heteroarylalkyl radicals are "lower tetravalent heteroarylalkyl" radicals having one or more tetravalent heteroaryl groups attached to an alkyl radical having 1 to 10 carbon atoms.

The term "alkylheteroarylalkyl" means a heteroarylalkyl radical substituted with one or more alkyl groups. Preferred alkylheteroarylalkyl radicals are "lower alkylheteroarylalkyl" radicals having alkyl moieties having from 1 to 10 carbon atoms.

The term "alkoxy" means an alkyl radical that is attached to the rest of the molecule by oxygen, such as a methoxy radical. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to 6 carbon atoms. Examples of such radicals are methoxy, ethoxy, propoxy, isopropoxy, butoxy and tertiary butoxy.

The term "carboxy" means a carboxy group, -CO ₂ H or salts thereof.

The term "carboxyalkyl" refers to an alkyl radical substituted with one or more carboxy groups. Preferred carboxyalkyl radicals are "lower carboxyalkyl" radicals with one or more carboxy groups attached to an alkyl radical having 1 to 6 carbon atoms.

The term "carboxyheterocycle" means a heterocycle radical substituted with one or more carboxy groups.

The term "carboxyheteroaryl" refers to a heteroaryl radical substituted with one or more carboxy groups.

The term "carboalkoxyalkyl" refers to an alkyl radical substituted with one or more alkoxycarbonyl groups. Preferred carboalkoxyalkyl radicals are "lower carboalkoxyalkyl" radicals having one or more alkoxycarbonyl groups attached to an alkyl radical having 1 to 6 carbon atoms.

The term "carboxyalkylamino" refers to an amino radical mono- or di-substituted with carboxyalkyl. Carboxyalkyl substituents are preferably "lower carboxyalkyl" radicals where the carboxy group is attached to an alkyl radical having 1 to 6 carbon atoms.

The term "active compound" means a compound of the present invention that inhibits the transport of bile acids.

When used in combination with "alkylaryl" or "arylalkyl", each of the above terms has the meanings indicated above.

The term "bile acid transport inhibitor" means a compound capable of inhibiting the absorption of bile acids from the intestine into the circulation of a mammal, such as a human. This not only increases fecal secretion of bile acids, but also reduces plasma or serum concentrations of cholesterol and cholesterol esters, and more particularly includes reducing LDL and VLDL cholesterol. Conditions or diseases in which prevention or treatment by bile acid transport inhibition are useful include hyperlipidemic conditions such as atherosclerosis.

compound

The compounds of the present invention may have two or more asymmetric carbon atoms and therefore comprise stereoisomers and racemates, such as diastereomers and enantiomers, in pure form and in mixtures. Such stereoisomers may be prepared by reacting the enantiomeric starting material using conventional techniques or by separating the isomers of the compounds of the present invention.

Isomers are geometric isomers such as cis isomers and trans isomers across double bonds. All such isomers are contemplated for the compounds of the present invention.

Compounds of the invention also include tautomers.

Compounds of the invention discussed below include salts, solvates and prodrugs thereof.

Compound synthesis

Starting materials for use in the preparation of the compounds of the present invention may be prepared by conventional methods known or known to those skilled in the art or in a manner similar to those disclosed in the art.

In general, the compounds of the present invention can be prepared by the procedure described below.

For example, as shown in Scheme 1, the reaction of aldehyde II with formaldehyde and sodium hydroxide produces hydroxyaldehyde III, which is described in Chem. BeR. 98, 728-734 (1965) is converted to mesylate IV using methanesulfonyl chloride and triethylamine in a similar manner to the procedure described. In the presence of triethylamine, the reaction of thiophenol V and mesylate IV prepared by the procedure described in WO 93/16055 yields ketoaldehyde VI, which is zinc and titanium 3 in reflux ethylene glycol dimethyl ether (DME). Two racemic stereoisomers of benzothiefine- (5H) -4-one VIII (if R ¹ and R ² are not equivalent) and 2,3-dihydrobenzothiene, cyclized with a reagent prepared from chloride Produces a mixture of VII. Oxidation of VII using 3 equivalents of m-chloro-perbenzoic acid (MCPBA) is 4-hydroxy-2,3,4,5-tetrahydrobenzothiene-1,1 upon hydrogenation with palladium on carbon as acid catalyst. 4 racemic stereoisomers of dioxide X and two racemic stereoisomers of 2,3,4,5-tetrahydro-benzothiene-1,1-dioxide XI (R ¹ and R ² are not equivalent) To produce a mixture of

The active compounds of the present invention use optically active starting materials III or are described in J. Org. Chem. , 39, 3904 (1974), former asc., 42, 2781 (1977) and former asc., 44,4891 (1979), can be prepared by redissolution of compound X with optical resolution agents well known to those skilled in the art.

On the other hand, ketoaldehyde wherein R ² is H can be prepared by the reaction of thiophenol V and 2-substituted acrolein.

Benzothiepin- (5H) -4-one VIII is oxidized with MCPBA to produce benzothiepin- (5H) -4-one-1,1-dioxide XII, which is reduced to sodium borohydride to 4 of X. Canine racemic stereoisomers are generated. Two stereoisomers of X, Xa and Xb having HO groups and R ⁵ on the opposite side of the benzothiene ring are reacted in methylene chloride with 40-50% sodium hydroxide in the presence of a phase transfer catalyst (PTC) to form a benzothiene ring Can be converted to the other two isomers of X, Xc and Xd with OH groups and R ⁵ on the same side of. The conversion can also be carried out using potassium t-butoxide in THF.

In the above scheme,

MCPBA = m-chloroperbenzoic acid

PTC = phase transfer catalyst

When R ¹ = butyl, R ² = ethyl, R ⁵ = phenyl, X = H, q = 4, 6a = Xa, 6b = Xb, 6c = Xc and 6d = Xd.

Compounds of the invention wherein R ⁵ is OR, NRR 'and S (O) _n R and R ⁴ is hydroxy can be prepared by the reaction of thiols, alcohols and amines with epoxide IX in which R ⁵ is H in the presence of a base Can be.

IX, when R ⁵ is H

Another route to Xc and Xd of the present invention is shown in Scheme 2. Compound VI is oxidized with 2 equivalents of m-chloroperbenzoic acid to give compound XIII. Hydrogenolysis of compound XIII to palladium on carbon yields compound XIV, which is cyclized using potassium t-butoxide or sodium hydroxide under phase transition conditions to give a mixture of Xc and Xd. Separation of Xc and Xd can be performed by HPLC or fractional crystallization.

Thiophenols XVIII and V used in the present invention can also be prepared according to Scheme 3. J. Chem. Soc., 2431-2432 (1958), alkylating phenol XV with arylmethyl chloride in a nonpolar solvent yields ortho substituted phenol XVI. Phenol XVI is described in J. Chem. Org. Chem., 31, 3980 (1966)] can be converted to thiophenol XVIII via thiocarbamate XVII. Phenol XVI is first reacted with dimethyl thiocarbamoyl chloride and triethylamine to give thiocarbamate XVII, rearranged by heat at 200-300 ° C., and then hydrolyzed the rearranged product with sodium hydroxide to thiophenol XVIII. Get Similarly, thiophenol V may also be prepared from 2-acylphenol XIX via intermediate thiocarbamate XX.

Scheme 4 shows another route to obtain benzothiefine-1,1-dioxide starting from thiophenol XVIII. Compound XVIII reacts with mesylate IV to produce sulfide-aldehyde XXI. Oxidation of XXI with 2 equivalents of MCPBA produces sulfone-aldehyde XIV, which is cyclized to potassium t-butoxide to give a mixture of Xc and Xd. In addition, cyclization of the sulfide-aldehyde with potassium t-butoxide gives a mixture of benzothiene XXII.

Examples of amine-containing and hydroxylamine-containing compounds of the present invention can be prepared as shown in Schemes 5 and 6. Reduction of 2-chloro-4-nitrobenzophenone with triethylsilane and trifluoromethane sulfonic acid affords 2-chloro-4-nitrodiphenylmethane 32. 32 is reacted with lithium sulfide, and the resulting sulfide is then reacted with mesylate IV to produce sulfide-aldehyde XXIII. Oxidation of XXIII with 2 equivalents of MCPBA yields sulfone-aldehyde XXIV, which can be hydrogenated to reduce to produce hydroxylamine XXV. Protection of hydroxyamine XXV with di-t-butyldicarbonei gives N, O-di- (t-butoxycarbonyl) hydroxyamino derivative XXVI. Cyclization of XXVI with potassium t-butoxide and removal of the t-butoxycarbonyl protecting group yields a mixture of hydroxylamino derivatives XXVIIc and XXVIId. Primary amines XXXIIIc and XXXIIId derivatives can also be prepared by further hydrogenation of XXIV or XXVIIc and XXVIId.

In Scheme 6, the sulfon-aldehyde XXV is reduced to hydrogen and then the resulting amino derivative is reduced alkylated with hydrogen and aldehyde (catalyzed by palladium on carbon in the same reaction vessel) to yield a substituted amine derivative XXVIII. . Cyclization of XXVIII with potassium t-butoxide yields the substituted amino derivatives XXIXc and XXIXd of the present invention.

Scheme 7 illustrates one method of introducing a substituent to an aryl ring at the 5-position of benzothiefine. Iodide 5-phenyl derivative XXX with iodine catalyzed by mercury triflate produces iodo derivative XXXI and produces carboxylate XXXII when performing palladium catalyzed carbonylation in alcohol. Hydrolysis of carboxylates and methods of inducing the resulting acids with acid derivatives are well known in the art.

The abbreviations used in the above description have the following meanings:

THF --- tetrahydrofuran

PTC --- Phase Transfer Catalyst

Aliquat 336 --- methyltricaprylylammonium chloride

MCPBA --- m-chloroperbenzoic acid

Celite --- brand name of diatomaceous earth filtration aid

DMF --- dimethylformamide

DME --- ethylene glycol dimethyl ether

BOC --- t-butoxycarbonyl group

Me --- methyl

Et --- ethyl

Bu --- butyl

EtOAc --- ethyl acetate

Et ₂ O --- diethyl ether

CH ₂ Cl ₂ --- methylene chloride

MgSO ₄ --- magnesium sulfate

NaOH --- Sodium Hydroxide

CH ₃ OH --- Methanol

HCl --- HCl

NaCl --- Sodium Chloride

NaH --- sodium hydride

NAH --- Lithium Aluminum Hydride

LiOH --- lithium hydroxide

Na ₂ SO ₃ --- Sodium sulfite

NaHCO ₃ --- Sodium Bicarbonate

DMSO --- dimethylsulfoxide

KOSiMe ₃ --- Potassium Trimethylsilanolate

PEG --- polyethylene glycol

MS --- Mass Spectroscopy

HRMS --- High Resolution Mass Spectroscopy

ES --- electrospray

NMR --- Nuclear Magnetic Resonance Spectroscopy

GC --- Gas Chromatography

MPLC --- Medium Pressure Liquid Chromatography

HPLC --- High Pressure Liquid Chromatography

RPHPLC --- Reverse High Pressure Liquid Chromatography

RT --- room temperature

h or hr --- time (s)

min --- min (s)

“Enriched with enantiomers” (e.e.) means that one set of enantiomers or diastereomers is superior to the corresponding set of enantiomers or diastereomers. Enantiomeric abundance of a mixture of enantiomers is calculated by dividing the predominant enantiomeric concentration by another enantiomeric concentration, multiplying it by 100 and expressing the result in%. The enantiomeric abundance may be about 1% to about 100%, preferably about 10% to about 100%, more preferably about 20% to 100%.

R ¹ and R ² may be selected from substituted and unsubstituted C ₁ -C ₁₀ alkyl, wherein the substituent (s) are C ₁ -C ₁₀ alkyl via alkylcarbonyl, alkoxy, hydroxy and ether linkages It may be selected from a nitrogen bearing heterocycle connected to. Substituents at 3-carbons include ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, -CH ₂ C (= 0) C ₂ H ₅ , -CH ₂ OC ₂ H ₅ and- CH ₂ O- (4-picolin). Preference is given to ethyl, n-propyl, n-butyl and isobutyl. In particularly preferably compounds of the invention, the substituents R ¹ and R ² are the same, for example n-butyl / n-butyl so that the compound is achiral at 3-carbons. Removing optical isomers from 3-carbons can simplify the selection, synthesis, separation and quality control of compounds used as ileal bile acid transport inhibitors in the ileum.

In both compounds with chiral 3-carbons and compounds with achiral 3-carbons, the substituents on the benzo ring (R ^x ) are hydrogen, aryl, alkyl, hydroxy, halo, alkoxy, alkylthio, alkylsulfinyl, alkylsul Ponyl, haloalkyl, haloalkoxy, (N) -hydroxy-carbonylalkyl amine, haloalkylthio, haloalkylsulfinyl, haloalkylsulfonyl, amino, N-alkylamino, N, N-dialkylamino, ( N) -alkoxycarbamoyl, (N) -aryloxycarbamoyl, (N) -aralkyloxycarbamoyl, trialkylammonium (particularly having halide counterions), (N) -amido, (N ) -Alkylamido, -N-alkylamido, -N, N-dialkylamido, (N) -haloalkylamido, (N) -sulfonamido, (N) -alkylsulfonamido, ( N) -haloalkylsulfonamido, carboxyalkylamino, trialkylammonium salts, (N) -carbamic acid, alkyl or benzyl esters, N-acylamines, hydroxylamines, haloacylamines, carbohydrates, one or more alkyl substituents Thiophene trialkyl ammonium salts with carboxylic acid or hydroxy substituents on the phase, alkylene bridges substituted with tetravalent ammonium salts,-[O (CH ₂ ) _w ] _x -X where x is 2 to 12 , w is 2 or 3 and X is a halo or tetravalent ammonium salt) and a (N) -nitrogen bearing heterocycle in which the nitrogen of the heterocycle may be tetravalent. Preferred species which may constitute R are methyl, ethyl, isopropyl, t-butyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, iodo, bromo, fluoro, methylsulfinyl, methyl sulfonyl, ethylthio, amino, hydroxylamine, N- methylamino, N, N- dimethylamino, N, N- diethylamino, (N) - benzyloxy carbamoyl, trimethylammonium, A ^-, -NHC (= O) CH ₃ , -NHC (= O) C ₅ H ₁₁ , -NHC (= O) C ₆ H ₁₃ , carboxyethylamino, (N) -morpholinyl, (N) -azetidinyl, ( N) -N- methyl pyridinium azepin T A ^-, (N) - pyrrolidinyl, pyrrolyl, (N) -N- methyl pyridinium A ^-, (N) -N- methyl-morpholinyl iodonium A ^-, and N, N'- methyl-piperazinyl, (N) - bromomethyl amido, (N) -N- hexylamino, _{^{thiophene, -N + (CH 3) 2}} CO 2 HI -, -NCH 3 CH 2 CO 2 H, - (N) -N'- dimethylpiperazine large uranium I ^-, (N) -t- butyloxy-carbamoyl, (N) - methyl sulfonamido, (N) N'- methylpyrrolidone and pyridinium- (OCH ₂ CH ₂ ) ₃ I (where A ⁻ is a pharmaceutically acceptable negative Ions). The benzo ring may be mono substituted at the 6, 7 or 8 positions or di substituted at the 7 and 8 positions. Also included are 6,7,8-trialkoxy compounds such as 6,7,8-trimethoxy compounds. Various other substituents may be advantageously present on the 6,7,8 and / or 9-positions of the benzo ring, such as guanidinyl, cycloalkyl, carbohydrates (eg, monosaccharides of 5 or 6 carbons), peptides and poly (oxyalkylene) is the ammonium salt 4 is connected to the ring via a connecting member, for _{example, - (OCH 2 CH 2)} x -N + R 13 R 14 R 15 a - ( wherein, x is from 2 to 10 being There is.

In a further compound of the invention, R ⁵ and R ⁶ are hydrogen and ring carbon substituted or unsubstituted aryl, thiophene, pyridine, pyrrole, thiazole, imidazole, pyrazole, pyrimidine, morpholine, N-alkyl Selected from pyridinium, N-alkylpiperazinium, N-alkylmorpholinium or furan, wherein the substituent (s) are halo, hydroxyl, trihaloalkyl, alkoxy, amino, N-alkylamino , N, N-dialkylamino, tetravalent ammonium salt, C ₁ to C ₄ alkylene bridge substituted with tetravalent ammonium salt, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyloxy and arylcarbonyloxy, ( O, O) -dioxyalkylene,-[O (CH) ₂ ] _W ] _X X (where x is 2 to 12, w is 2 or 3, X is halo or tetravalent ammonium salt, thiophene, Pyridine, pyrrole, thiazole, imidazole, pyrazole or furan). The aryl group of R ⁵ or R ⁶ is preferably phenyl, phenylene or benzene triyl, ie can be unsubstituted, mono substituted or di substituted. Species which may constitute a substituent on the aryl ring of R ⁵ or R ⁶ include fluoro, chloro, bromo, methoxy, ethoxy, isopropoxy, trimethylammonium (preferably with iodine or chlorinated counterions) , Methoxycarbonyl, ethoxycarbonyl, formyl, acetyl, propanoyl, (N) -hexyldimethylammonium), hexylenetrimethylammonium, tri (oxyethylene) iodine and tetra (oxyethylene) trimethylammonium iodide Ids, each of which is substituted at the p-position, the m-position or both of the aryl rings. Other substituents that may be present on phenylene, benzene triyl or other aromatic rings include 3,4-dioxymethylene (5-membered ring) and 3,4-dioxyethylene (6-membered ring). Among the compounds that may or may prove to have preferred ileal bile acid transport inhibitory, R ⁵ or R ⁶ is phenyl, p-fluorophenyl, m-fluorophenyl, p-hydroxyphenyl, m-hydroxyphenyl, p-methoxyphenyl, m-methoxyphenyl, pN, N-dimethylaminophenyl, mN, N-dimethylaminophenyl, I ^- p- (CH ₃ ) ₃ -N ⁺ -phenyl, I ^- m- (CH ₃ ) ₃ -N ⁺ -phenyl, I ^- m- (CH ₃ ) ₃ -N ⁺ -CH ₂ CH _2- (OCH ₂ CH ₂ ) ₂ -O-phenyl, I ^- p- (CH ₃ ) ₃ -N ⁺ -CH ₂ CH _2- (OCH ₂ CH ₂ ) -O-phenyl, I ^- m- (N, N-dimethylpiperazinium)-(N ')-CH _2- (OCH ₂ CH ₂ ) -O-phenyl , 3-methoxy-4-fluorophenyl, thienyl-2-yl, 5-chlorothienyl-2-yl, 3,4-difluorophenyl, I ^- p- (N, N-dimethylpiperage Nium)-(N ')-CH _2- (OCH ₂ CH ₂ ) -O-phenyl, 3-fluoro-4-methoxyphenyl, -4-pyridinyl, 2-pyridinyl, 3-pyridinyl, N In -methyl-4-pyridinium, IN-methyl-3-pyridinium, 3,4-dioxymethylenephenyl, 3,4-dioxyethylenephenyl and p-methoxycarbonylphenyl There is a selection from. Preferred compounds include 3-ethyl-3-butyl and 3-butyl-3-butyl compounds having each of the above preferred R ⁵ substituents together with the R ^x substituents shown in Table 1. Particular preference is given to only one but not both of R ⁵ and R ⁶ being hydrogen.

It is particularly preferred that R ⁴ and R ⁶ are hydrogen, R ³ and R ⁵ are not hydrogen, and R ³ and R ⁵ are oriented in the same direction relative to the plate of the molecule, ie both in α or both in β form. . When R ² is butyl and R ¹ is ethyl, it is more preferred that R ¹ has the same orientation with respect to the plates of the molecule, such as R ³ and R ⁵ .

Table 1A provides a list of exemplary species of R ¹ / R ² , R ⁵ / R ^6, and R ^x .

Another R group R ¹ , R ² R ³ , R ⁴ R ⁵ (R ^x ) q ethyl HO- Ph 7-methyl n-propyl H- p-F-Ph 7-ethyl n-butyl m-F-Ph 7-isopropyl n-pentyl p-CH ₃ O-Ph- 7-3 tert-butyl n-hexyl p-CH ₃ O-Ph- 7-OH Isopropyl m-CH ₃ O-Ph- 7-OCH ₃ Isobutyl p- (CH ₃ ) ₂ N-Ph- 7-O (isopropyl) Isopentyl m- (CH ₃ ) ₂ N-Ph- 7-SCH ₃ CH ₂ C (= 0) C ₂ H _{5 ^{I -, p- (CH 3)}} 3 -N + -Ph- 7-SOCH ₃ CH ₂ C ₂ H _{5 ^{I -, m- (CH 3)}} 3 -N + -Ph- 7-SO ₂ CH ₃ CH ₂ CH (OH) C ₂ H _{5 ^{I -, p- (CH 3)}} 3 -N + -CH 2 CH 2 - (OCH 2 CH 2) 2 -O-Ph- 7-SCH ₂ CH ₃ CH ₂ O- (4-picolin) _{^{I -, m- (CH 3)}} 3 -N + -CH 2 CH 2 - (OCH 2 CH 2) 2 -O-Ph- 7-NH ₂ I ^-, p- (N, N- dimethylpiperazine) - (N ') - CH 2 - (OCH 2 CH 2) 2 -O-Ph- 7-NHOH I ^-, m- (N, N- dimethylpiperazine) - (N ') - CH 2 - (OCH 2 CH 2) 2 -O-Ph- 7-NHCH ₃ mF, p-CH ₃ O-Ph-3,4-dioxymethylene-Ph 7-N (CH ₃ ) ₂ m-CH ₃ O-, pF-Ph-4-pyridine _{^{7-N + (CH 3)}} 3, I - N-methyl-4-pyridinium, I ^- 3-pyridine 7-NHC (= O) CH ₃ N-methyl-3-pyridinium, I ^- 2-pyridine 7-N (CH ₂ CH ₃ ) ₂ p-CH ₃ O ₂ C-Ph-thienyl-2-yl _{7-NMeCH 2 CO 2 H,} I - 5-Cl-thienyl-2-yl 7- (N) -morpholine

R ¹ , R ² R ³ , R ⁴ R ⁵ (R ^x ) q 7- (N) -azetidine 7- (N) -N- methyl-azepin tea pyridinium, I ^- 7- (N) -pyrrolidine 7- (N) -N- methyl-pyrrolidin-pyridinium, I ^- 7- (N) -N- methyl-morpholinyl titanium, I ^- 7- (N) -N'-methylpiperazine 7- (N) -N'- dimethyl Pierre Large titanium, I ^- 7-NH-CBZ 7-NHC (O) C ₅ H ₁₁ 7-NHC (O) CH ₂ Br 7-NH-C (NH) NH ₂ 7- (2) -thiophene 8-methyl 8-ethyl 8-isopropyl 8-3 tertiary butyl 8-OH 8-OCH ₃ 8-O (isopropyl) 8-SCH ₃ 8-SOCH ₃ 8-SO ₂ CH ₃ 8-SCH ₂ CH ₃ 8-NH ₂ 8-NHOH 8-NHCH ₃ 8-N (CH ₃ ) _{2 ^{8-N + (CH 3)}} 2, I - 8-NHC (= O) CH ₃ 8-N (CH ₂ CH ₃ ) ₂ 8-NMeCH ₂ CO ₂ H _{^{8-N + (Me) 2}} CH 2 CO 2 H, I - 8- (N) -morpholine 8- (N) -azetidine 8- (N) -N- methyl-azepin tea pyridinium, I ^- 8- (N) -pyrrolidine 8- (N) -N- methyl-morpholinyl titanium, I ^- 8- (N) -N'-methylpiperazine

R ¹ , R ² R ³ , R ⁴ R ⁵ (R ^x ) q 8- (N) -N'- dimethylpiperazine large titanium, I ^- 8-NH-CBZ 8-NHC (O) C ₅ H ₁₁ 8-NHC (O) CH ₂ Br 8-NH-C (NH) NH ₂ 8- (2) -thiophene 9-methyl 9-ethyl 9-isopropyl 9-3 tertiary butyl 9-OH 9-OCH ₃ 9-O (isopropyl) 9-SCH ₃ 9-SOCH ₃ 9-SO ₂ CH ₃ 9-SCH ₂ CH ₃ 9-NH ₂ 9-NHOH 9-NHCH ₃ 9-N (CH ₃ ) _{2 ^{9-N + (CH 3)}} 2, I - 9-NHC (= O) CH ₃ 9-N (CH ₂ CH ₃ ) ₂ 9-NMeCH ₂ CO ₂ H _{^{9-N + (Me) 2}} CH 2 CO 2 H, I - 9- (N) -morpholine 9- (N) -azetidine 9- (N) -N- methyl-azepin tea pyridinium, I ^- 9- (N) -pyrrolidine 9- (N) -N- methylpyrrolidin-pyridinium, I ^- 9- (N) -N- methyl-morpholinyl titanium, I ^- 9- (N) -N'-methylpyrazine 9- (N) -N'- dimethylpiperazine large titanium, I ^- 9-NH-CBZ 9-NHC (O) C ₅ H ₁₁ 9-NHC (O) CH ₂ Br 9-NH-C (NH) NH ₂ 9- (2) -thiophene

R ¹ , R ² R ³ , R ⁴ R ⁵ (R ^x ) q 7-OCH ₃ , 8-OCH ₃ 7-SCH ₃ , 8-OCH ₃ 7-SCH ₃ , 8-SCH ₃ 6-OCH ₃ , 7-OCH ₃ , 8-OCH ₃

Another preferred compound of the present invention includes a core structure having two or more pharmaceutically active benzothiene structures covalently bonded to the core portion via a functional group linkage as described above. Such active benzothiene structures preferably include the following:

[Formula DIV

[Formula DIVA]

In the above formula,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^x , q and n are as defined above and R ⁵⁵ is a covalent bond or arylene.

The core portion is selected from the group consisting of alkane diyl, alkene diyl, alkyne diyl, polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrates, amino acids, peptides and polypeptides, wherein alkane diyl, alkene diyl, alkyn diyl , Polyalkane diyl, alkoxy diyl, polyether diyl, polyalkoxy diyl, carbohydrates, amino acids, peptides and polypeptides are O, NR ⁷ , N ⁺ R ⁷ R ⁸ , S, SO, SO ₂ , S ⁺ R ⁷ R ⁸ , May have one or more carbon atoms replaced by PR ⁷ , P ⁺ R ⁷ R ⁸ , phenylene, heterocycle, tetravalent heterocycle, tetravalent heteroaryl or aryl,

Alkanes Diyl, Alkenes Diyl, Alkynes Diyl, Polyalkanes Diyl, Alkoxy Diyl, Polyether Diyl, Polyalkoxy Diyl, Carbohydrates, Amino Acids, Peptides and Polypeptides are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl , Cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , P (O) R ^{13 R 14, P + R 13} R 14 R 15 a -, P (OR 13) OR 14, S + R 13 R 14 a - , and ^{N + R 9 R 11 R 12} a - is independently selected from the group consisting of May be substituted with one or more substituents,

The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be,

Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene group can EK.

Examples of core parts include:

In the above formulas,

R ²⁵ is selected from the group consisting of C and N,

R ²⁶ and R ²⁷ are independently selected from the group consisting of the following groups;

Among these groups, R ²⁶ , R ²⁹ , R ³⁰ and R ³¹ are independently selected from alkyl, alkenyl, alkylaryl, aryl, arylalkyl, cycloalkyl, heterocycle and heterocycloalkyl,

A ⁻ is a pharmaceutically acceptable anion and k is 1-10.

In compounds of formula (DIV), R ²⁰ , R ²¹ , R ²² in formulas (DII) and (DIII) and R ²³ in formula (DIII) may be bonded to R ¹⁹ at any of the 6-, 7-, 8- or 9-positions thereof. Can be.

In another embodiment, the core moiety backbone R ¹⁹ is a core moiety backbone with at least four active benzothiene side units as discussed in Formulas DII and DIII, ie R ²⁰ , R ²¹ , R ²² and R ²³ as discussed above. It can be substituted in large quantities through multiple functional groups within. The core portion backbone unit R ¹⁹ may comprise a multimer mixture of one core portion unit, its multimers and the different core portion units discussed herein, ie alone or in combination. The individual core portion backbone units may range from about 1 to about 100, preferably from about 1 to about 80, more preferably from about 1 to about 50 and more preferably from about 1 to about 25. The number of attachment points of similar or different active benzothiene side units in a single core portion backbone unit is about 1 to about 100, preferably about 1 to about 80, more preferably about 1 to about 50, more Preferably from about 1 to about 25. Such point of attachment may comprise a bond to C, S, O, N or P within the scope of any of the groups included in the definition of R ¹⁹ .

More preferred benzothiene moieties comprising R ²⁰ , R ²¹ , R ²² and / or R ²³ follow the preferred structure outlined above for Formula (I). The 3-carbons on each benzothiene moiety are achiral and the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may be selected from combinations of the preferred groups and substituents discussed above. The core structure may, for example, comprise poly (oxyalkylene) or oligo (oxyalkylene), in particular poly (oxyethylene) or oligo (oxyethylene) or poly (oxypropylene or oligo (oxypropylene).

Dosage, Formulation, and Route of Administration

The ileal bile acid transport inhibitor compound of the present invention is for preventing or treating hyperlipidemia diseases or symptoms by any manner of contacting the compound with the site of action of the ileum of a mammal such as a human, for example, orally. Can be administered.

For the prevention or treatment of the above mentioned diseases or symptoms, the compounds of the present invention may be used as they are.

However, pharmaceutically acceptable salts are more water soluble than the parent compound and are therefore particularly suitable for drug administration. It is obvious that such salts should have pharmaceutically acceptable anions or cations. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, if possible, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid, and organic acids such as acetic acid, benzenesulfur. Derived from phonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isotionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, toluenesulfonic acid, tartaric acid and trifluoroacetic acid There is a salt. Chloride salts are particularly preferred for drugs. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (eg, sodium and potassium salts), and alkaline earth metal salts (eg, magnesium and calcium salts).

It is a matter of course that the anion belonging to the definition of A ^{− in} the present invention should also be pharmaceutically acceptable, and may also be selected from the examples described above.

The compounds of the present invention may be provided in the form of a pharmaceutical composition with an acceptable carrier. The carrier must of course be acceptable in that it is compatible with the other ingredients of the composition and must not be harmful to the patient. The carrier may be solid or liquid or a combination thereof, and is preferably formulated with the compound as a unit dose of a composition, such as a tablet, which may comprise from 0.05% to 95% of the active compound. It may also include other pharmacologically active substances, including other compounds of the invention. The pharmaceutical composition of the present invention mainly consists of mixing the components, but can be prepared by techniques known in the pharmaceutical art.

The compounds of the present invention can be administered in any conventional manner useful for use with medicaments, either as individual therapeutic compounds or as complex therapeutic compounds.

The amount of compound needed to achieve the desired biological effect will of course depend on many factors such as the particular compound chosen, the intended use, the mode of administration and the clinical condition of the patient.

In general, the daily dosage ranges from about 0.3 to about 100 mg / kg body weight / day, preferably about 1 to about 50 mg / kg body weight / day, more preferably about 3 to about 10 mg / kg body weight / Day range. This total daily dose may be administered to the patient as a single dose or as divided multiple subdoses. The subdose may be administered 2 to 6 times a day. Dosages may be sustained release effective to achieve the desired result.

Oral dosage unit dosage formulations, such as tablets or capsules, may comprise, for example, from about 0.1 to about 100 mg, preferably from about 1 to about 75 mg, more preferably from about 10 to about 50 mg of a benzothiefine compound. have. In the case of pharmaceutically acceptable salts, the aforementioned weight means the weight of the benzothiene ions derived from the salt.

Oral delivery of ileal bile acid transport inhibitors described herein can include agents known in the art that can prolong or sustain delivery of the drug to the gastrointestinal tract through a variety of mechanisms. Such delivery may include pH sensitive release of the dosage form based on pH changes in the small intestine, slow erosion of the tablet or capsule, intestinal retention based on the physical properties of the formulation, bioadhesion of the dosage form to the mucosal lining of the intestine, or dosage forms. There is enzymatic release of the active drug. Its purpose effect is to manipulate the dosage form to prolong the time that the active drug molecule is delivered to the site of action (ileum). Therefore, enteric-coated preparations and enteric-release sustained-release preparations are also within the scope of the present invention. Suitable enteric skins include cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester.

When administered intravenously, the dosage will range from, for example, about 0.1 to 1.0 mg / kg body weight, preferably about 0.25 mg / kg body weight to about 0.75 mg / kg body weight, more preferably about 0.4 to about 0.6 mg / kg body weight. Can be. This dosage may conveniently be administered as an infusion ranging from about 10 ng / kg body weight / minute to about 100 ng / kg body weight / minute. Infusion fluids suitable for this purpose may include, for example, from about 0.1 ng to about 10 mg / ml, preferably from about 1 ng to about 10 mg / ml. Unit dosages may include, for example, about 1 mg to about 10 g of a compound of the present invention. Thus, the ampoule for injection may, for example, comprise about 1 mg to about 100 mg.

The pharmaceutical compositions described herein may be oral, rectal, topical, buccal (eg sublingual) and parenteral, although the most suitable route for a given case may vary depending on the nature and severity of the therapeutic disease and the nature of the particular compound used. Compositions suitable for oral (eg, transdermal, intramuscular, intradermal or intravenous) administration. In most cases the preferred route of administration is oral.

Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, cassettes, lozenges or tablets each containing a predetermined amount of one or more compounds described herein; As powder or granules; As a solvent or suspending agent in an aqueous or non-aqueous liquid; Or as oil-in-water or water-in-oil emulsions. As shown, such compositions may be prepared by any suitable method known in the art of pharmacy, including the step of mixing the active compound with a carrier (which may include one or more accessory ingredients). Generally, the composition is prepared by homogeneously and homogeneously mixing the active compound with a liquid or finely divided solid carrier, or a combination thereof, and then molding, if necessary. For example, tablets may be made by compressing or molding the powders or granules of the compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compression of a compound in free flowing form, such as a powder or granules, optionally with a binder, lubricant, inert diluent and / or surfactant / dispersant, and compressed in a suitable machine. Molded tablets may be prepared by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.

Pharmaceutical compositions suitable for buccal (sublingual) administration include lozenges comprising the compounds of the invention in a flavoring base, typically sucrose and gum arabic or tragacanth, and the compounds are genlatin and glycerin or sucrose and arabian. There is pastille included in an inert base such as rubber.

Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous formulations of the compounds described herein. The agent may be administered via transdermal, intramuscular or intradermal injection, but is preferably administered intravenously. Such formulations may be conveniently prepared by mixing the compound with water and the resulting solution is sterilized and isotonic with blood. Injectable compositions of the invention generally comprise from 0.1 to 5% w / w of a compound disclosed herein.

Pharmaceutical compositions suitable for rectal administration are preferably provided as unit dosage suppositories. Suppositories can be prepared by mixing the compounds of the invention with one or more conventional solid carriers such as cocoa butter and then molding the resulting mixture.

Pharmaceutical compositions suitable for topical administration to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers that can be used include petrolatum, lanolin, polyethylene glycol, alcohols and mixtures of two or more thereof. The concentration of the active compound is generally 0.1-15% w / w of the composition, such as 0.5-2%.

Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration may be provided as discrete patches adapted to provide intimate contact with the epidermis of a patient for long periods of time. Such patches are suitable for the addition of the compounds of the invention to an optionally buffered aqueous solution, dissolved and / or dispersed in an adhesive, or dispersed in a polymer. Suitable concentrations of the active compound are about 1% to 35%, preferably about 3% to 15%. As one particular possibility, the compounds of the present invention may be delivered from a patch by electrotransportation or iontophoresis as described, for example, in Pharmaceutical Research, 3 (6), 318 (1986).

In any case, the amount of active ingredient that can be mixed with the carrier material to produce the sole dosage form to be administered depends on the host treated and the particular mode of administration.

Solid dosage forms for oral administration, including the capsules, tablets, pills, powders, and granules described above, include one or more compounds of the present invention in admixture with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms may also include other substances besides inert diluents, such as lubricants such as magnesium stearate, as in general practice. In the case of capsules, tablets and pills, the dosage form may further comprise a buffering agent. Tablets and pills may be further prepared as enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solvents, suspensions, syrups and elixirs, including inert diluents commonly used in the art, such as water. Such compositions may further comprise adjuvants such as wetting agents, emulsifiers and suspending agents, and sweetening, flavoring and fragrances.

Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared according to the known art using suitable dispersing or curing and suspending agents. Sterile injectables may also be sterile injectable solutions or suspensions in nontoxic parenterally acceptable diluents or solvents, such as solvents in 1,3-butanediol. Acceptable excipients and solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. Oils that can be used for this purpose include any mild nonvolatile oil, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables.

Pharmaceutically acceptable carriers include those described above.

Treatment regimen

Dosages for using the compounds and / or compositions of the invention to prevent, rescue or alleviate disease states with hyperlipidemia as a factor of the disease, such as atherosclerosis, or to prevent or treat high cholesterol levels in plasma or blood. The regimen is chosen according to various factors. The factors include the type, age, weight, sex, food and medical condition of the patient, the severity of the disease, the route of administration, the pharmacological considerations such as the activity, efficacy, pharmacokinetics and toxicology profile of the specific compound used, the drug. Whether a delivery system is used, and whether a compound of the invention is administered as part of a combination drug. Therefore, the dosage regimen actually used varies widely and may differ from the preferred dosage regimes described above.

Initial treatment of patients with symptoms of hyperlipidemia can begin with the dosages described above. Treatment can generally continue for weeks or months or years as needed until hyperlipidemic disease symptoms are controlled or eliminated. Patients treated with the compounds or compositions disclosed herein can be routinely monitored by measuring serum cholesterol concentrations to investigate therapeutic effects, such as by any of the methods known in the art. Continuous analysis of these data allows the compound of the present invention to be administered in an optimally effective amount at any point in time, and also to change the treatment regimen during the treatment to determine the duration of the treatment. In this way, the treatment regimen / dose schedule may be changed appropriately during the course of treatment so that a minimum amount of ileal bile acid transport inhibitor according to the present invention can be administered that exhibits a satisfactory effect and is administered only as long as necessary to successfully treat hyperlipidemia. Can last.

The following examples are intended to illustrate various aspects of the invention and are not intended to limit the invention.

Synthetic Procedure Examples

Preparation method 1

2-ethyl-2- (mesyloxymethyl) hexan (1)

In a low temperature (10 ° C.) solution in which 12.6 g (0.11 mol) of methanesulfonyl chloride and 10.3 g (0.13 mol) of triethylamine were dissolved, the reaction temperature was maintained at 30 ° C. or lower, as described in Chem. Ber. 98, 728-734 (1965)] was added dropwise 15.8 g of 2-ethyl-2- (hydroxymethyl) hexanal prepared according to the procedure described in the following. The reaction mixture was stirred at rt for 18 h, quenched with dilute HCl and extracted with methylene chloride. The methylene chloride extract was dried over MgSO ₄ and concentrated in vacuo to give 24.4 g of a brown oil.

Preparation method 2

2-((2-benzoylphenylthio) methyl) -2-ethylhexan (2)

31 g (0.144 mol) of 2-mercaptobenzophenone, 24.4 g (0.1 mol) of 2-ethyl-2- (mesyloxymethyl) -hexan (1), triethyl, prepared according to the procedure described in WO 93/16055 A mixture of 14.8 g (0.146 mol) amine and 80 ml 2-methoxyethyl ether was maintained at reflux for 24 hours. The reaction mixture was added to 3N HCl and extracted with 300 ml of methylene chloride. The methylene chloride layer was washed with 300 mL of 10% NaOH, dried over MgSO ₄ and concentrated in vacuo to remove 2-methoxyethyl ether. The residue was purified by HPLC (10% EtOAc-hexane) to give 20.5 g (58%) of the title compound (2).

Scheme 6

General Reaction Scheme X

General Scheme X: Nucleophilic substitution of suitably substituted 2-fluorobenzaldehyde with lithium sulfide or other nucleophilic sulfide anions in polar solvents (e.g. DMF, DMA, DMSO, etc.), followed by dialkyl mesylate aldehyde (X) Dialkyl benzene dialdehyde Y was added by addition. This dialdehyde was DIBAL reduced at low temperature to obtain benzyl alcohol monoaldehyde Z. This benzyl alcohol was converted to benzyl bromide and then the sulfide was oxidized with sulfone to obtain the main intermediate W.

In addition, the compounds of the present invention can be synthesized using cyclic sulfate (XL, described below) as a reagent, as shown in Schemes XI and XII. The following example illustrates the procedure using cyclic sulfate as a reagent.

Scheme XI illustrates another route for obtaining benzothiepine-1,1-dioxide, specifically 3,3-dialkyl analogues, using thiophenol XVIIIA as starting material. Thiophenol XVIIIA can be reacted with cyclic sulfate XL to give alcohol XLI, which can be oxidized to produce aldehyde XLII. Aldehyde XLII itself can be further oxidized to produce sulfone XLIII, and the sulfone can be cyclicized to obtain stereoisomeric mixtures of benzothiene XLIVa and XLIVb.

Thiophenol XVIIIA can be prepared according to Scheme 3 as described above, and is represented by the following formula.

Formula XVIIIA

In this formula, R ⁵ , R ^x and q are as described above for the compound represented by the formula (I). Cyclic sulfate XL can be prepared according to synthetic procedures known in the art and represented by the following formula.

Formula XL

In this formula, R ¹ and R ² are as described above for the compound represented by the formula (I). R ¹ and R ² are preferably alkyl, more preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl, and more More preferably R ¹ and R ² are n-butyl.

In the method of Scheme XI, thiophenol XVIIIA is reacted with cyclic sulfate XL for the first time. This reaction is preferably carried out in an aprotic solvent such as methoxyethyl ether. Although reaction conditions such as temperature and time are not exact, it is preferred to proceed the reaction at approximately room temperature for about 2 hours. It is preferred to use starting materials in approximately stoichiometric proportions for this reaction, but it is preferred that the cyclic sulfate XL is slightly excess. That is, about 1.01 to 1.3 equivalents of cyclic sulfate XL per equivalent of thiophenol XVIIIA present can be used to improve reaction time and yield. More preferably, this ratio is about 1.1 equivalents of cyclic sulfate XL per equivalent of thiophenol XVIIIA present.

In the process of the invention, thiophenol XVIIIA is also treated with extractant. The extractant may be added to the solvent containing thiophenol XVIIIA before, concurrently or after the addition of the cyclic sulfate XL. Without wishing to be bound by a particular theory, the extractant is believed to remove hydrogen atoms from the mercaptan group bonded to the benzene ring of thiophenol XVIIIA. The sulfur anion of the thiophenol obtained is then reacted with cyclic sulfate XL to cleave the sulfate ring. The sulfur anion of thiophenol is bonded to the terminal carbon atom of the cleaved ring sulfate. The terminal group at the unbonded end of the cleaved ring sulfate is a sulfate group.

Extractants are generally bases having a pH of about 10 or greater. As this base, alkali metal hydrides, such as sodium hydride, lithium hydride, or potassium hydride, are preferable, and sodium hydride is especially preferable. The extractant is preferably slightly excess relative to thiophenol XVIIIA. That is, using about 1.0 to about 1.1 equivalents of extractant per equivalent of thiophenol XVIIIA present can improve reaction time and yield. More preferably, the proportion is about 1.1 equivalents of extractant per equivalent of thiophenol XVIIIA present.

The sulfate group of the intermediate product obtained by the reaction of thiophenol XVIIIA with cyclic sulfate XL is preferably removed by hydrolysis to give alcohol XLI. Suitable hydrolysing agents include inorganic acids, in particular hydrochloric acid and sulfuric acid.

Several reactions, including thiophenol XVIIIA, cyclic sulfate XL, extractant and hydrolysing agent, can be carried out in situ without the need to separate any intermediates produced.

Alcohol XLI is then separated by conventional methods (eg extraction with aqueous methyl salicylate) and then oxidized to aldehyde XLII using standard oxidants. The oxidizing agent is preferably sulfur trioxide or pyridinium chloro chromate, more preferably pyridinium chloro chromate. The reaction is carried out in a suitable organic solvent such as methylene chloride or chloroform.

The aldehyde XLII is then also separated by conventional methods and further oxidized to sulfone-aldehyde XLIII using standard oxidants. The oxidant is preferably metachloroperbenzoic acid.

The sulfone-aldehyde XLIII is likewise isolated in a conventional manner and then cyclized to form stereoisomeric benzothiene pins XLIVa and XLIVb. The cyclic agent is preferably a base having a pH between about 8 and about 9. More preferably an alkoxide base, even more preferably tert-butoxylated.

The second stage of oxidation of Scheme XI can be reversed if it does not affect the overall reaction. Alcohol XLI may be oxidized to produce sulfone-alcohol first, and then further oxidized to produce sulfone-aldehyde.

Scheme XII illustrates another route to produce benzothiefine-1,1-dioxide, especially 3,3-dialkyl analogues, using halobenzene L as starting material. Halobenzene L can react with cyclic sulfate XL described above to produce alcohol LI, which can be oxidized to produce sulfone-alcohol LII. The sulfone-alcohol LII itself may be further oxidized to produce sulfone-aldehyde LIII, which may then be cyclized to produce a stereoisomer mixture of benzothiefine LIVa and LIVb.

Halobenzene L (commercially available or synthesized from commercially available halobenzenes by those skilled in the art) is represented by the following formula.

Formula L

Wherein R ⁵ , R ^x and q are as described above for compounds of formula I, R ^h is a halogen such as chloro, bromo, fluoro or iodo and R ^e is in the ortho or para position of halobenzene As the electron leaving group present, it is preferable that it is p-nitro or o-nitro group. Cyclic sulfate XL may be prepared as described above in Scheme XI, and may be represented by the following formula.

Formula XL

In this formula, R ¹ and R ² are as described above for the compound represented by the formula (I). R ¹ and R ² are preferably alkyl, more preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and pentyl, even more Preferably R ¹ and R ² are n-butyl.

In the process of Scheme XII, halobenzene L is first reacted with cyclic sulfate XL. This reaction is preferably carried out in an aprotic solvent such as dimethyl formamide or N: N-dimethylacetamide, with dimethyl formamide being particularly preferred. Although reaction conditions such as temperature and time are not exact, it is preferred that the reaction proceeds between about 70 ° C and about 90 ° C for about 8-12 hours. More preferably, the reaction temperature is maintained at about 80 ° C. It is preferred to use starting materials in approximately stoichiometric proportions for this reaction, but it is preferred that the cyclic sulfate XL is slightly excess. In other words, about 1.1 to 1.3 equivalents of cyclic sulfate XL per equivalent of halobenzene L present can be used to improve reaction time and yield. More preferably, this ratio is about 1.1 equivalents of cyclic sulfate XL per equivalent of halobenzene L present.

In the process of the invention, halobenzene L is also treated with extractant. The extractant may be added to the solvent containing halobenzene before, simultaneously with, or after addition of the cyclic sulfate XL. While not wishing to be bound by any theory, it is believed that the extractant removes halogen atoms bonded to the benzene ring of halobenzene L and substitutes divalent sulfur atoms for that atom. The resulting sulfur anion then reacts with cyclic sulfate XL to cleave the sulfate ring. The sulfur anion of halobenzene binds to the terminal carbon atom of the cleaved ring sulfate. The terminal group at the unbonded end of the cleaved ring sulfate is a sulfate group. In general, dialkali metal sulfide is used as the extractant, and in particular, dilithium sulfide is preferable. The extractant is preferably slightly excess relative to halobenzene L. That is, about 1.01 to about 1.3 equivalents of extractant per equivalent of halobenzene L present can be used to improve reaction time and yield. More preferably, the ratio is about 1.05 equivalent of extractant per 1 equivalent of halobenzene L present.

The sulfate group of the product obtained by the reaction of thiophenol XVIIIA with cyclic sulfate XL is preferably removed by hydrolysis to give a mixture of ester and alcohol LI. Suitable hydrolysing agents are inorganic acids, in particular hydrochloric acid and sulfuric acid. The ester is then converted to alcohol L1 by treatment with an alkali metal hydroxide, preferably sodium hydroxide.

Several reactions, including halobenzene L, cyclic sulfate XL, extractant and hydrolysing agent, can be carried out in situ without the need to separate any intermediates produced.

The alcohol LI is then separated by conventional methods and oxidized to sulfone-alcohol LII using a standard oxidant. The oxidant is preferably metachloroperbenzoic acid. This reaction is carried out in a suitable organic solvent such as methylene chloride or chloroform.

The sulfone-alcohol LII is then separated by conventional methods and further oxidized to sulfone-aldehyde LIII using standard oxidants. The oxidizing agent is preferably sulfur trioxide or pyridinium chlorochromate, and more preferably pyridinium chlorochromate. This reaction is carried out in a suitable organic solvent such as methylene chloride or chloroform.

The sulfone-aldehyde XLIII is then converted to the desired benzothiene-1,1-dioxide according to the procedure described in Scheme XI.

The two stage oxidation reaction can be reversed as long as it does not affect the total reaction. That is, alcohol XLI may be oxidized first to produce aldehydes, and then aldehydes may be oxidized to produce sulfone-aldehydes.

The use of cyclic sulfate reagents in place of the mesylate reagents used in Schemes XI and XII increases the overall yield and solves many of the purification problems associated with the reaction schemes that proceed through the mesylate intermediate. Total yield is markedly increased by using cyclic sulfate instead of mesylate reagent. In addition, the intermediate product produced during the cyclic sulfate coupling step of this reaction does not need to be chromatographically separated. For example, the intermediates produced in Schemes XI and XII are water soluble alkali metal salts and impurities can be removed upon ether extraction. This intermediate is then hydrolyzed to the desired alcohol.

Examples corresponding to Scheme XI

Step 1: Preparation of 2,2-dibutyl-1,3-propanediol

Dibutyl diethylmalonate (150 g, 0.55 mol) (Aldrich) was dissolved in dry THF (700 mL) while maintaining the temperature of the reaction mixture between about -20 ° C and about 0 ° C using an acetone / dry ice bath. To the stirred solution was added lithium aluminum hydride (662 mL, 1.2 equiv, 0.66 mol) in 662 mL 1M THF. The reaction mixture was then stirred at rt overnight. The reaction was cooled to −20 ° C. and 40 mL of water, 80 mL of 10% NaOH and 80 mL of water were added dropwise. The resulting suspension was filtered. The filtrate was dried over sodium sulfate and concentrated in vacuo to give 98.4 g (95% yield) of the title diol as an oil. The product was confirmed by proton NMR, carbon NMR and MS.

Step 2: Dibutyl-cyclic Sulfite

The solution of dibutyl diol (103 g, 0.5478 mol) obtained in step 1 in anhydrous methylene chloride (500 mL) and triethylamine (221 g, 4 equiv, 2.19 mol) was stirred at 0 ° C. under nitrogen. To this mixture thionyl chloride (97.78 g, 0.82 mol) was added dropwise. Within 5 minutes the solution turned yellow and then turned black when the addition was complete within about 30 minutes. The reaction was completed within 3 hours (gas chromatography confirmed the consumption of starting material). The mixture was washed twice with ice water and twice with brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give 128 g (100% yield) of dibutyl-cyclic sulfite as a black oil. NMR and MS were consistent with the product.

Step 3: Dibutyl-cyclic Sulfate

Ruthenium (III) chloride (1 g) and sodium periodate (233 g, 1.08 mol) in a solution of dibutyl-cyclic sulfite in step 2 dissolved in 500 ml of water cooled in an ice bath and 600 ml of acetonitrile under a nitrogen atmosphere. Was added. The reaction was stirred overnight and the color of the solution turned black. It was confirmed by gas chromatography that no starting material remained. The mixture was extracted once with 300 ml of ether and three times with brine. The organic phase was dried over magnesium sulphate and passed through celite. The filtrate was concentrated in vacuo to give 133 g (yield 97.8%) of dibutyl-cyclic sulfate as an oil. The product was confirmed by proton NMR, carbon NMR and MS.

Step 4: 2-[(2-4'-fluorobenzyl-4-methylphenylthio) methyl] -2-butylhexanol

60% oil dispersion (0.27 g, 6.68 mmol) of sodium hydride was washed with hexane. The hexane was decanted and 20 mL of methoxyethyl ether was added to the washed sodium hydride and cooled in an ice bath. A mixture of diphenylmethane thiophenol (1.55 g, 6.68 mmol) in 10 ml of methoxyethyl ether was added dropwise over 15 minutes. Then, a mixture of dibutyl-cyclic sulfate (2.17 g, 8.66 mmol) of step 3 was added to 10 ml of methoxyethyl ether. The resulting mixture was stirred at 0 ° C. for 30 minutes and then at room temperature under nitrogen atmosphere for 1 hour. Gas chromatography confirmed no thiol remained. The solvent was evaporated, washed with water and then twice with ether. The aqueous layer was separated and 20 mL of 10% NaOH was added. This aqueous mixture was heated for 30 minutes, then cooled, acidified with 6N HCl and then heated for 10 minutes. The mixture was cooled and extracted with ether. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 2.47 g of hexanol (yield 92.5%) as an oil. The product was confirmed by proton NMR, C13-NMR and MS.

Step 5: 2-[(2-4'-fluorobenzyl-4-methylphenylthio) methyl] -2-butylhexanal

Pyridinium chlorochromate (2.18 g, 9.9 mmol) was added to a solution of hexanol (2 g, 4.9 mmol) in step 4 dissolved in 40 ml of methylene chloride while cooling in an ice bath under a nitrogen atmosphere. The reaction mixture was stirred for 3 hours and filtered through silica gel. The filtrate was concentrated in vacuo to give 1.38 g (70% yield) of hexanal as an oil. The product was confirmed by proton NMR, carbon NMR and MS.

Step 6: 2-[(2-4'-fluorobenzyl-4-methylphenylsulfonyl) methyl] -2-butylhexanal

70% metachloroperbenzoic acid (0.54 g, 2.2 mmol) was added to a solution of hexanal (0.44 g, 1.1 mmol) in step 5 dissolved in 20 ml of methylene chloride while cooling in an ice bath under a nitrogen atmosphere. The reaction mixture was stirred for 18 hours and filtered. The filtrate was washed successively with 10% NaOH (3X), water and brine, dried over magnesium sulfate and concentrated in vacuo to give 0.42 g (90% yield) of hexanal as an oil. The product was confirmed by proton NMR, carbon NMR and MS.

Step 7: cis-3,3-dibutyl-7-methyl-5- (4'-fluoro-phenyl) -2,3,4,5-tetrahydrobenzothiene-1,1-dioxide

The mixture in which hexanal (0.37 g, 0.85 mmol) of step 6 was added to 30 mL of dry THF was stirred in an ice bath at a temperature of about 0 ° C. Then tert-butoxide potassium potassium (102 mg, 0.85 mmol) was added. After 3 hours, thin layer chromatography confirmed the formation and the presence of small amounts of starting material. The crude reaction mixture was acidified with 10% HCl, extracted with ether, washed successively with water and brine, dried over MgSO ₄ and concentrated in vacuo. This concentrate was purified by HPLC (10% EtOAc-hexanes). The first fraction was 0.1 g of starting material in oil form and the second fraction yielded 0.27 g (75% yield) of the desired benzothiene as a white solid. The product was confirmed by proton NMR, carbon NMR and MS (M + H = 433).

Examples corresponding to Scheme XII

Step 1: 2-[(2-4'-methoxybenzyl-4-nitrophenylthio) -methyl] -2-butylhexanol

Chlorodiphenylmethane (10 g) was dissolved in 25 mL of DMF and lithium sulfide (1.75 g, 1.05 equiv) was added. The solution turned red. The reaction mixture was heated at 80 ° C. overnight. The solution was cooled to 0 ° C. and dibutyl-cyclic sulfate (9.9 g; prepared as in step 3 of Scheme XI Example) in 10 ml of DMF was added and stirred overnight at room temperature. The solvent was evaporated and washed successively with water and ether (three times). The aqueous layer was separated, 40 mL of concentrated sulfuric acid was added, and the reaction mixture was heated overnight. The mixture was cooled down and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated in vacuo. The product was heated with 3M NaOH for 1 hour. The mixture was cooled and extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over magnesium sulfate and concentrated in vacuo. The concentrate was dissolved in methylene chloride, filtered through silica gel, eluted with 20% ethyl acetate and hexanes and concentrated in vacuo to give 11.9 g (74% yield) of hexanol as an oil. The product was confirmed by proton NMR, C13-NMR and MS.

Step 2: 2- [2-4'-methoxybenzyl-4-nitrophenylthio) -methyl] -2-butylhexanal

70% MCPBA (8.261 g, 33 mmol) was added to a solution of hexanol (6 g, 13 mmol) in step 1 dissolved in 50 ml of methylene chloride while cooling in an ice bath under a nitrogen atmosphere. The reaction was stirred at rt for 18 h and filtered. The filtrate was washed successively with 10% NaOH (3X), water and brine, dried over magnesium sulfate and concentrated in vacuo. The concentrate was dissolved in methylene chloride, eluted with 20% ethyl acetate and hexane through silica gel, filtered and concentrated in vacuo to give 5 g (77.7% yield) of hexanal as a white solid (MP 58-60 ° C.). The product was confirmed by proton NMR, C13-NMR and MS.

Example 1398

Step 1. Preparation of Compound 2

4.7 g (28.6 mmol) of 3-nitrobenzeneboronic acid and tetrakis (triphenylphosphine) were dissolved in a solution of dibutyl 4-fluorobenzene dialdehyde (14.3 mmol) in Example 1395 in 72 mL of toluene and 54 mL of ethanol. ) 0.8 g (0.7 mmol) of palladium (0) and 45 mL of 2M aqueous sodium carbonate solution were added. This heterogeneous mixture was refluxed for 3 hours, then cooled to room temperature and fractionated with ethyl acetate and water. The organic layer was dried over MgSO ₄ and concentrated in vacuo. Purification by silica gel chromatography using ethyl acetate / hexanes (25/75) gave 4.8 g (73%) of the title compound as a yellow solid. ¹ H NMR (CDC1 ₃ ) d 0.88 (t, J = 7.45 Hz, 6H), 0.99-1.38 (m, 8H), 1.62-1.75 (m, 2H), 1.85-2.00 (m, 2H), 3.20 (s , 2H), 4.59 (s, 2H), 6.93 (dd, J = 10.5 and 2.4 Hz, lH), 7.15 (dt, J = 8.4 and 2.85 Hz, lH), 7.46-7.59 (m, 2H), 8.05- 8.16 (m, 3 H), 9.40 (s, l H).

Step 3. Preparation of Compound 3

A solution of 4.8 g (10.4 mmol) of Compound 2 in 500 mL of THF was cooled to 0 ° C. in an ice bath. 20 ml of 1 t solution of potassium t-butoxide was added slowly while maintaining at < After stirring was continued for 30 minutes, the reaction was stopped by adding 100 ml of saturated ammonium chloride solution. The mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography over a 100 ml plug using CH ₂ Cl ₂ as eluent gave 4.3 g (90%) of the title compound 3 as a pale yellow foam. ¹ H NMR (CDC1 ₃ ) d 0.93 (t, J = 7.25 Hz, 6H), 1.00-1.55 (m, 8H), 1.59-1.74 (m, 3H), 2.15-2.95 (m, lH), 3.16 (qAB , JAB = l5.0 Hz, AV = 33.2 Hz, 2H), 4.17 (d, J = 6.0 Hz, lH), 5.67 (s, lH), 6.34 (dd, J = 9.6 and 3.0 Hz, 1H), 7.08 (dt, J = 8.5 and 2.9 Hz, lH), 7.64 (t, J = 8.l Hz, lH), 7.81 (d, J = 8.7 Hz, lH), 8.l3 (dd, J = 9.9 and 3.6 Hz, lH), 8.23-8.30 (m, lH), 8.44 (s, lH). MS (FABH ⁺ ) m / e (relative strength) 464.5 (l00), 446.6 (65). Calcd for HRMS M + H 464.1907. Found 464.1905.

Step 4. Preparation of Compound 4

8.2 g (182 mmol) of dimethyl amine was added to a cooled (0 ° C.) solution in which Compound 3 (4.3 g, 9.3 mmol) contained in a stainless steel reaction vessel was dissolved in 30 mL of THF. The vessel was sealed and heated to 110 ° C. for 16 hours. The reaction vessel was cooled to room temperature and the contents were concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-2000) using an ethyl acetate / hexanes gradient (10-40% ethyl acetate) afforded 4.0 g (88%) of the title compound 4 as a yellow solid. ¹ H NMR (CDC1 ₃ ) d 0.80-0.95 (m, 6H), 0.96-1.53 (m, 8H), 1.60-1.69 (m, 3H), 2.1l-2.28 (m, 1H), 2.79 (s, 6H ), 3.09 (qAB, JAB = 15.0 Hz, DV = 45.6 Hz, 2H), 4.90 (d, J = 9.0 Hz, lH), 5.65 (s, lH), 5.75 (d, J = 2.l Hz, lH ), 6.52 (dd, J = 9.6 and 2.7 Hz 1 lH), 7.59 (t, J = 8.4 Hz, lH), 7.85 (d, J = 7.80 Hz, lH), 7.89 (d, J = 9.0 Hz, lH) , 8.20 (dd, J = 8.4 and l.2 Hz, lH), 8.43 (s, 1H). MS (FABH ⁺ ) m / e (relative strength) 489.6 (100), 471.5 (25). Calcd for HRMS M + H 489.2423. Found 489.2456.

Step 5. Preparation of Compound 5

To a suspension of Compound 4 (1.0 g, 2.1 mmol) contained in a stainless steel Parr reactor in 100 ml of ethanol was added 1 g of 10% palladium on carbon. The reaction vessel was sealed and purged twice with H ₂ , then H ₂ (100 psi) was charged and heated to 45 ° C. for 6 h. The reaction vessel was cooled to room temperature and the contents were filtered to remove the catalyst. The filtrate was concentrated in vacuo to afford the title compound 5 (0.9 g, 96%). ¹ H NMR (CDC1 ₃ ) d 0.80- 0.98 (m, 6H), 1.00-1.52 (m, 10H), 1.52-1.69 (m, lH), 2.15-2.29 (m, lH), 2.83 (S, 6H) , 3.07 (qAB, JAB = 15.l Hz, DV = 44.2 Hz, 2H), 3.70 (s, 2H), 4.14 (s, lH), 5.43 (s, lH), 6.09 (d, J = 2.4 Hz, lH), 6.52 (dd, J = 12.2 and 2.6 Hz, lH), 6.65 (dd, J = 7.8 and l.8 Hz, lH), 6.83 (s, lH), 6.93 (d, J = 7.50 HZ, lH ), 7.19 (t, J = 7.6 Hz, lH), 7.89 (d, J = 8.9 Hz, lH). MS (FABH ⁺ ) m / e (relative intensity) 459.7 (100). Calcd for HRMS M + H 459.2681. Found 459.2670.

Step 6. Preparation of Compound 6

To a solution of compound 5 (914 mg, 2.0 mmol) in 50 mL of THF was added 800 mg (4.0 mmol) of 5-bromovaleroyl chloride. Then 4 g (39.6 mmol) of TEA were added. The reaction was stirred for 10 minutes and then fractionated with ethyl acetate and brine. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography over 70 mL MPLC column using an eluent gradient of ethyl acetate (20-50%) in hexanes gave the title compound 6 (0.9 g, 73%) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) d 0.84-0.95 (m, 6H), 1.02-l.53 (m, 10H), 1.53-1.68 (m, lH), 1.80-2.00 (m, 4H), 2.12-2.26 ( m, 4H), 2.38 (t, J = 6.9 Hz, 2H), 2.80 (S, 6H), 3.07 (qAB, JAB = 15.6 Hz, DV = 40.4 Hz, 2H), 3.43 (t, J = 6.9 Hz, 2H), 4.10 (s, lH), 5.51 (s, lH), 5.95 (d, J = 2.4 Hz, lH), 6.5l (dd, J = 9.3 and 2.7 Hz, lH), 7.28 (s, lH) , 7.32-7.4 l (m, 2H), 7.78 (d, J = 8.l Hz, lH), .7.90 (d, J = 9.0 Hz, lH).

Step 7. Preparation of Compound 7

18 g (178 mmol) of TEA was added to a solution of Compound 6 (0.9 g, 1.45 mmol) in 25 mL of acetonitrile. Heated at 55 ° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by reverse phase silica gel chromatography (Waters Delta Prep 3000) using an acetonitrile / water gradient containing 0.05% TFA (20-65% acetonitrile) gave the title compound 7 (0.8 g, 73%) as a white foam. Got it. ¹ H NMR (CDC1 ₃ ) d 0.80-0.96 (m, 6H), 0.99-1.54 (m, 19H), 1.59-1.84 (m, 3H), 2.09-2.24 (m, lH), 2.45-2.58 (m, 2H), 2.81 (s, 6H), 3.09 (qAB, JAB = 15.6 Hz, DV = 18.5 Hz, 2H), 3.13-3.31 (m, 8H), 4.16 (s, lH), 5.44 (s, lH), 6.08 (d, J = 1.8 Hz, lH), 6.57 (dd, J = 9.3 and 2.7 Hz, lH), 7.24 (t, J = 7.5 Hz, lH), 7.34 (t, J = 8.4 Hz, lH), 7.56 (d, J = 8.4 Hz, lH), 7.74 (s, lH), 7.88 (d, J = 9.0 Hz, 1H), 9.22 (s, lH). HRMS calcd 642.4304; Found 642.4343.

Example 1398a

Step 1

Under an inert atmosphere, 68.3 g (0.328 mol, Aldrich 15, 777-5) phosphorus was weighed into a 500 mL two-neck round bottom flask. The N ₂ inlet adapter of the flask was fitted and suva sealed. N ₂ purge was initiated by removal from the inert atmosphere. 50 ml of anhydrous chlorobenzene (Aldrich 28, 451-3) were added to PCl ₅ via a syringe and stirring was started with a magnetic stir bar.

60 g of 2-chloro-5-nitrobenzoic acid (0.298 mol, Aldrich 12, 511-3) were weighed. It was added slowly to the chlorobenzene solution with N ₂ purification. Stir overnight at room temperature. After stirring at room temperature for about 20 hours, it was placed in an oil bath and heated at 50 ° C. for 1 hour. Chlorobenzene was removed under high vacuum. The residue was washed with anhydrous hexane. The acid chloride was dried (61.95 g). Store in an inert, dry atmosphere.

The acid chloride was dissolved in 105 mL (0.97 mol, Aldrich 29, 629-5) anhydrous in an inert atmosphere. This solution was injected into a 500 ml two-neck round bottom flask.

45.1 g (0.34 mol, Aldrich 29,471-3) of aluminum chloride were weighed and added via a solid addition funnel. Fit an addition funnel and N ₂ inlet adapter to the reaction flask. After removal from the inert atmosphere, the reaction solution was cooled in an ice bath and N ₂ purge was initiated. AlCl ₃ was slowly added to the cooled solution. After all was added, it heated up to room temperature. Stir overnight.

The reaction was added to 300 ml of 1N HCl and ice solution to stop the reaction. Stir for 15 minutes. Extract twice with ether. The organic layers were combined, extracted twice with 2% NaOH, and then extracted twice with deionized water. Dehydrated with MgSO ₄ , filtered, and rotary evaporated to dryness. The anisole was separated under high vacuum. The product was crystallized from 90% ethanol and 10% ethyl acetate. NMR and mass spectrum analysis (m / z = 292).

Step 2

38.10 g (0.131 mol) of the benzophenone obtained in step 1 were dissolved in 250 ml of anhydrous methylene chloride. It was added to a 3 liter flask equipped with N ₂ inlet, addition funnel and stopper. Stir with a magnetic stir bar. The solution was cooled in an ice bath.

A solution in which 39.32 g (0.262 mol, Aldrich 15, 853-4) of trifluoromethane sulfonic acid was dissolved in 170 ml of anhydrous methylene chloride was prepared. Injection through an addition funnel was added dropwise to the cooled solution under N ₂ . After all the addition was stirred for 5 minutes.

A solution in which 22.85 g (0.197 mol, Aldrich 23, 019-7) of triethyl silane was dissolved in 170 ml of anhydrous methylene chloride was prepared. Injection through an addition funnel was added dropwise to the cooled solution under N ₂ . After all the addition was stirred for 5 minutes.

A second solution in which 39.32 g of trifluoromethane sulfonic acid was dissolved in 170 ml of anhydrous methylene chloride was prepared. Injection through an addition funnel was added dropwise to the cooled solution under N ₂ . After all the addition was stirred for 5 minutes.

A second solution in which 22.85 g of triethyl silane was dissolved in 170 ml of anhydrous methylene chloride was prepared. Injection through an addition funnel was added dropwise to the cooled solution under N ₂ . After all was added, the temperature was gradually raised to room temperature overnight. Stir overnight under N ₂ .

1300 mL of saturated NaHCO ₃ was prepared in a 4 liter beaker. Cool in an ice bath. The reaction mixture was added slowly with vigorous stirring. Stirred at cooled temperature for 30 minutes. Separation was done by injection through a separatory funnel. The organic layer was separated and the aqueous layer was extracted twice with methylene chloride. The organic layer was dried over MgSO ₄ . Crystallized from ethanol. It was dried in a vacuum tube. Anhydrous weight = 28.8 g. Confirmed by NMR and mass spectrum (m / z = 278).

Step 3

Product 2 (10.12 g, 0.036 mol) was dissolved in 200 mL of anhydrous DMSO. Injected into a 500 ml round bottom flask equipped with a magnetic stir bar. The flask was equipped with a water cooler, N ₂ inlet, and stop cap. 1.84 g of Li ₂ S (0.040 mol, Aldrich 21, 324-1) was added. The flask was placed in an oil bath, heated to 75 ° C. overnight under N ₂ and then cooled to room temperature.

10.59 g of dibutyl mesylate (0.040 mol) was weighed. It was dissolved in anhydrous DMSO and added to the reaction solution. Fully purged with N ₂ and heated to 80 ° C. overnight.

Cool to room temperature. 500 ml of 5% acetic acid was prepared in a 2 liter beaker. The reaction mixture was added slowly while stirring. Stir for 30 minutes. Extracted three times with ether. The organic layers were combined and extracted with water and saturated NaCl. The organic layer was dehydrated with MgSO ₄ , filtered and then rotary evaporated to dryness. The oil was dried in a vacuum tube. Purification product was obtained by column chromatography using 95% hexane and 5% ethyl acetate as mobile phase. Anhydrous weight = 7.8 g. NMR and mass spectra were measured (m / z = 444).

Step 4

Product 3 (9.33 g, 0.021 mol) was dissolved in 120 mL of anhydrous methylene chloride. Injected into a 250 ml round bottom flask equipped with a magnetic stir bar. The flask was equipped with an N ₂ inlet and stopper. The solution was cooled in an ice bath under N ₂ purification. 11.54 g (0.0435 mol, Fluka 25800, about 65%) 3-chloroperbenzoic acid was added slowly. After the addition was complete, the temperature was raised to room temperature and the reaction was monitored by TLC. The reaction rapidly converted to the sulfoxide intermediate, but it took 8 hours to convert to sulfone. The solution was cooled overnight in the freezer. The solid was filtered off from the reaction and the filtrate was extracted with 10% K ₂ CO ₃ . The organic layers were combined and dehydrated with MgSO ₄ . It was dried by filtration and rotovap. Crystallization from ethanol or separation by column chromatography gave the purification product. NMR and mass spectrum analysis (m / z = 476).

Step 5

The reaction was carried out in a 300 ml stainless steel Parr stirred mini reactor. Product 4 (9.68 g, 0.0204 mol) was added to the bottom of the reactor. 160 ml of ethanol were added. For safety reasons, the following two compounds were added in an N ₂ atmospheric glove bag. In a glove bag, 15.3 ml (0.204 mol, Aldrich 25, 254-9, about 37% aqueous solution) of formaldehyde and 1.45 g of 10% Pd / carbon (Aldrich 20, 569-9) were added. The reactor was sealed before being taken out of the glove bag. The reactor was purged three times with H ₂ . Heated to 55 ° C. under H ₂ . H ₂ 200 psig, and the reaction allowed to proceed at 55 ℃ was stirred at a speed of 250rpm. It was carried out overnight under these conditions.

The reactor was cooled down and H ₂ was degassed. The reaction progress was checked by TLC. The reaction was a mixture of the desired product and the intermediate. The reaction mixture was filtered through celite washing well with ether. Rotary evaporation and redissolution with ether. Extracted with water. The organic layer was dehydrated with MgS0 ₄ , filtered and rotary evaporated to dryness. It was dried on a vacuum tube.

The same amount was again injected into the reactor, sealed, and the reaction was allowed to proceed overnight under the same conditions. After the second run the reactions were all converted to the desired product. The reaction was cooled and the H ₂ pressure was degassed. Purified with N ₂ . Filter through celite washing well with ether. Dry by rotary evaporation. It was dissolved in ether and extracted with water. The organic layer was dehydrated with MgS0 ₄ , filtered and rotary evaporated to dryness. It was dried on a vacuum tube. NMR and mass spectra were analyzed (m / z = 474).

Step 6

Product 5 (8.97 g, 0.0189 mol) was dissolved in 135 mL of dry THF. Injected into a 250 ml round bottom flask equipped with a magnetic stir bar. The flask was equipped with an N ₂ inlet and stopper. The solution was cooled in an ice / salt bath under N ₂ purification. 2.55 g (0.227 mol, Aldrich 15, 667-1) potassium t-butoxide were added slowly. After complete addition, stirring was continued at −10 ° C. while being monitored by TLC. Immediately after completion of the reaction, 10% HCl was added to stop the reaction and stirred for 10 minutes. Extracted three times with ether. The organic layer was dehydrated with MgS0 ₄ , filtered and rotary evaporated to dryness. Recrystallized from ether. NMR and mass spectrum analysis (m / z = 474).

Step 7

Product 6 (4.67 g, 0.01 mol) was dissolved in 100 mL of anhydrous chloroform. Injected into a 250 ml round bottom flask equipped with a magnetic stir bar. The flask was fitted with an N ₂ inlet adapter and suva sealed. The solution was cooled in a dry ice / acetone bath under N ₂ purification. Boron tribromide (2.84 mL, 0.03 mol, Aldrich 20, 220-7) was slowly added via syringe. After stirring at low temperature for 15 minutes, the temperature was raised to room temperature. The reaction progress was monitored by TLC. The reaction was usually completed within 3 hours.

The solution was cooled in an ice bath. The reaction was stopped with 100 ml of 10% K ₂ CO ₃ with rapid stirring. After stirring for 10 minutes, it was separated by moving through a separatory funnel. The aqueous layer was removed. The organic layer was extracted once with 10% HCl, H ₂ O and saturated NaCl solution. The organic layer was dehydrated with MgSO ₄ , filtered and rotovap dried. The product was crystallized from ether. NMR and mass spectrum analysis (m / z = 460).

Step 8

0.38 g (9.57 mmol, Aldrich 19, 923-0, 60% dispersion in mineral oil) were weighed into a 250 mL round bottom flask equipped with a magnetic stir bar. The flask was equipped with an N ₂ inlet and a stopper stopper. NaH was cooled in an ice bath and N ₂ clarification was initiated. 60 mL of anhydrous DMF and product 7 (4.0 g, 8.7 mmol) were dissolved. Stir at low temperature for 30 minutes. 1.33 g (9.57 mmol, Fischer P-208) K ₂ CO ₃ was added.

16.1 g (43.5 mmol, Aldrich 33,343-3) of 1,2-bis- (2-iodoethoxy) ethane were dissolved in 60 mL of anhydrous DMF. It was added to the cooled reaction mixture. After warming to room temperature, it was heated at 40 ° C. overnight under N ₂ .

Diluted with ether and washed with successive extractions with 5% NaOH, H ₂ O and saturated NaCl. The organic layer was dehydrated with MgSO ₄ , filtered and dried. The product was purified by column chromatography using 75% hexane and 25% ethyl acetate as mobile phase. NMR and mass spectrum analysis (m / z = 702).

Step 9

Product 8 (1.0 g, 1.43 mmol) was dissolved in 10 mL of anhydrous acetonitrile. Injected into a 3 oz Fischer-Porter pressure reaction vessel equipped with a magnetic stir bar. 2.9 g of triethyl amine (28.6 mmol, Aldrich 23, 962-3) dissolved in 10 ml of anhydrous acetonitrile was added. After fully purifying with N ₂ , the reaction system was sealed. Heated to 45 ° C. The reaction was monitored by TLC. The reaction was usually completed within 48 hours.

Cleared by removing acetonitrile under vacuum. Redissolved with anhydrous chloroform and the tertiary ammonium salt precipitated with ether. This was repeated 3 to 5 times. Drying gave a crystalline product. NMR and mass spectrum analysis (m / z = 675).

Example 1399

Step 1. Preparation of Compound 1

120 g (641 mmol) of 2-bromobenzyl alcohol was added slowly through an addition funnel to a solution in which 144 g (2560 mmol) of KOH was dissolved in 1.1 L of DMSO. Then, 182 g (80 mL, 1282 mmol) of methyl iodide was added through an addition funnel. Stir at room temperature for 15 minutes. The reaction was added to 1.0 L of water and extracted three times with ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated in vacuo. Silica gel chromatography purification through a 200 ml plug using hexane (100%) as eluent gave compound 1 (103.2 g, 80%) as a clear colorless liquid. ¹ H NMR (CDC1 ₃ ) d 3.39 (s, 3H), 4.42 (s, 2H), 7.18-7.27 (m, 2H), 7.12 (d, J = 7.45, lH), 7.50 (s, lH).

Step 2. Preparation of Compound 2

240 ml of 2.5 M n-butyl lithium (576 mmol) was added to a cooled (-78 ° C) solution in which Compound 1 (95 g, 472 mmol) was dissolved in 1.5 L of THF. After the mixture was stirred for 1 hour, a solution in which 180 g (566 mmol) of zinc iodide was dissolved in 500 ml of THF was added. The mixture was stirred for 30 minutes, warmed to 5 ° C., then cooled to −10 ° C., and 6 g of Pd (PPh ₃ ) ₄ (5.2 mmol) and 125 g of 2,5-difluorobenzoyl chloride (708 mmol) were added. It was. The mixture was stirred at room temperature for 18 hours, cooled to 10 ° C., quenched with water, fractionated with ethyl acetate and water, and the organic layer was washed with 1N HCl and 1N NaOH. The organic layer was dried over MgSO ₄ and concentrated in vacuo. Silicagel chromatography purification using 5% ethyl acetate / hexane as eluent gave the title compound 2 (53.6 g, 43%) as an orange oil. ¹ H NMR (CDCl ₃ ) d 3.40 (s, 3H), 4.51 (s, 2H), 7.12-7.26 (m, 3H), 7.47 (t, J = 7.50, lH), 7.57 (d, J = 7.45, lH), 7.73 (d, J = 7.45, lH), 7.80 (s, lH).

Step 3. Preparation of Compound 3

A solution of Compound 2 (53 g, 202.3 mmol) and Li ₂ S 11.2 g (242.8 mmol) in DMF 250 mL was heated to 100 ° C. for 18 hours. The reaction was cooled (0 ° C.) and 60.7 g of a solution of Compound X (cyclic sulphate compound of Example 1397) (242.8 mmol) dissolved in 50 mL of DMF was added. Stirred at room temperature for 18 hours and concentrated in vacuo. 1 L of water was added to the organic residue and extracted twice with diethyl ether. The aqueous layer was acidified (pH 1) and refluxed for 2 days. After cooling to room temperature, extracted with methylene chloride, the organic layer was dried over MgSO ₄ and concentrated in vacuo. Purification of silica gel chromatography (Waters Prep-500) using 10% ethyl acetate / hexane as eluent gave the title compound 3 (42.9 g, 48%) as a yellow oil. ¹ H NMR (CDC1 ₃ ) d 0.86 (t. J = 7.25 Hz, 6H), 1.10-l.26 (m, 12H), 2.83 (s, 2H), 3.32 (s, 2H), 3.40 (s, 3H ), 4.48 (s, 3H), 7.02 (dd, J = 8.26 Hz and 2.82 Hz, lH), 7.16 (dt, J = 8.19 Hz and 2.82 Hz, lH), 7.45 (t, J = 7.65 Hz, lH) , 7.56-7.61 (m, 2H), 7.69 (d, J = 7.85 Hz, lH), 7.74 (s, lH).

Step 4. Preparation of Compound 4

To a cooled (40 ° C.) solution of compound 3 (42.9 g, 96.2 mmol) dissolved in 200 ml of methylene chloride, 21.6 g (12.8 ml, 144 mmol) of trifluoromethane sulfonic acid was added, followed by 22.4 g (30.7) of triethyl silane. Ml, 192.4 mmol) was added. After stirring for 2 hours at -20 ℃, the reaction was stopped with water and warmed to room temperature. Fractionated with methylene chloride and water, the organic layer was dried over MgSO _{4 and} concentrated in vacuo. Silicagel chromatography (Waters Prep-500) purification using 10% ethyl acetate / hexane as eluent gave the title compound 4 (24.2 g, 60%) as an oil. ¹ H NMR (CDC1 ₃ ) d 0.89 (t, J = 7.05 Hz, 6H), 1.17-1.40 (m, 12H), 1.46 (t, J = 5.84 Hz, lH), 2.81 (s, 2H), 3.38 ( s, 3H), 3.43 (d, J = 5.23 Hz, 2H), 4.16 (s, 2H), 4.42 (s, 2H), 6.80 (d, J = 9.67 Hz, lH), 6.90 (t, J = 8.46 Hz, lH), 7.09 (d, J = 7.45 Hz, lH), 7.15-7.21 (m, 2H), 7.25 -7.32 (m, 2H), 7.42 (m, lH).

Step 5. Preparation of Compound 5

31.2 g (195 mmol) of sulfur trioxide pyridine complex was added to a cooled (15-18 ° C.) solution in which Compound 4 (24.2 g, 55.8 mmol) was dissolved in 100 mL of DMSO. Stirred at room temperature for 30 minutes. Added to cold water and extracted three times with ethyl acetate. The organic layer was washed with 5% HCl (300 mL) and then brine (300 mL), dried over MgSO ₄ and concentrated in vacuo to afford the title compound 5 (23.1 g, 96%) as a light brown oil. ¹ H NMR (CDCl ₃ ) d 0.87 (t, J = 7.05 HZ, 6H), 1.01-1.32 (m, 8H), 1.53-1.6S (m, 4H), 2.98 (s, 2H), 3.38 (s, 3H), 4.15 (s, 2H), 4.43 (s, 2H), 6.81 (dd, J = 9.66 Hz and 2.82 Hz, lH), 6.9 l (t, J = 8.62 Hz, lH), 7.07 (d, J = 7.46 Hz, lH), 7.14 (s, lH), 7.19 (d, J = 7.65 Hz, lH), 7.26-7.32 (m, lH), 7.42 (dd, J = 8.66 Hz and 5.64 Hz, lH), 9.40 (s, lH).

Step 6. Preparation of Compound 6

To a cooled (0 ° C.) solution in which Compound 5 (23.1 g, 53.6 mmol) was dissolved in 200 ml of methylene chloride, 28.6 g (112.6 mmol) of metachloroperoxy-benzoic acid was added. Stir at room temperature for 24 hours. The reaction was quenched with 100 ml of 10% Na ₂ SO ₃ and fractionated with water and methylene chloride. The organic layer was dried over MgSO ₄ and concentrated in vacuo to afford the title compound 6 (24.5 g, 98%) as a pale yellow oil. ¹ H NMR (CDCl ₃ ) d 0.86-1.29 (m, l4H), 1.58-l.63 (m, 2H), 1.82-1.91 (m, 2H), 3.13 (s, 2H), 3.39 (s, 3H) , 4.44 (s, 2H), 4.50 (s, 2H), 6.93 (d, J = 9.07 Hz, lH), 7.10-7.33 (m, 5H), 8.05 (s, lH), 9.38 (s, lH).

Step 7. Preparation of Compound 7

In a stainless steel reaction vessel, 100 ml of 2.0 M dimethylamine solution and 20 ml of pure dimethyl amine were added to a solution of Compound 6 (24.5 g, 52.9 mmol) in 20 ml of THF. The vessel was sealed, cooled to room temperature and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500) using 15% ethyl acetate / hexanes gave the title compound 7 (21.8 g, 84%) as a clear colorless oil. ¹ H NMR (CDC1 ₃ ) d 0.85 (t, J = 7.25 Hz, 6H), 0.93-1.29 (m, 8H), 1.49-1.59 (m, 2H), 1.70 -1.80 (m, 2H), 2.98 (s , 8H), 3.37 (s, 3H), 4.41 (s, 2H), 4.44 (s, 2H), 6.42 (s, lH), 6.58 (dd, J = 9.0 Hz and 2.61 Hz, lH), 7.13 (d , J-7.45 Hz, lH), 7.21 (s, lH), 7.28 (t, J = 7.85 Hz, lH), 7.82 (d, J = 9.06 Hz, lH), 9.36 (S, lH).

Step 8. Preparation of Compound 8

The solution of Compound 7 (21.8 g, 44.8 mmol) dissolved in 600 mL of THF was cooled to 0 ° C. While maintaining the temperature at <5 ° C, 58.2 ml of 1M t-potassium butoxide solution was slowly added. After stirring for 30 minutes, the reaction was stopped with 50 ml of saturated ammonium chloride solution. The organic layer was partitioned between ethyl acetate and water, dried over MgSO ₄ and concentrated in vacuo. Purification by recrystallization from about 10% ethyl acetate / hexanes gave the title compound 8 (15.1 g) as a white solid. The mother liquor was purified by silica gel chromatography (Waters Prep-500) using 30% ethyl acetate / hexane as eluent to yield the title compound 8 (3.0 g) as a white solid. MS (FABLi ⁺ ) m / e 494.6. HRMS (EI ⁺ ) calcd for M + H 487.2756. Found 487.2746.

Step 9. Preparation of Compound 9

The solution of Compound 8 (2.0 g, 4.1 mmol) dissolved in 20 ml of methylene chloride was cooled to -60 ° C. 4.1 ml of 1 M boron tribromide solution was added. Stirred at room temperature for 30 minutes. The reaction was cooled to about 10 ° C. and quenched with 50 mL of water. The organic layer was partitioned between methylene chloride and water, dried over MgSO ₄ and concentrated in vacuo. Purification by recrystallization from 50% ethyl acetate / methylene chloride gave the title compound 9 (1.95 g, 89%) as a white solid. MS (FABH ⁺ ) m / e 537. Calcd for HRMS (FAB) M 536.1834. Found 536.1822.

Step 10. Preparation of Compound 10

The solution of Compound 9 (1.09 g, 2.0 mmol) and pyridine 4.9 g (62 mmol) in 30 ml of acetonitrile was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. Purification by recrystallization from methanol / dietal ether gave the title compound 10 (1.19 g, 96%) as off-white solid. MS (FAB ⁺ ) m / e 535.5.

Example 1400

Step 1

A 12 liter four necked round bottom flask was equipped with a reflux condenser, N ₂ gas adapter, mechanical stirrer and addition funnel. This system was purified with N ₂ . A slurry in which sodium hydride (126.0 g / 4.988 mol) was dispersed in toluene (2.5 L) was added, and the mixture was cooled to 6 ° C. A solution of 4-fluorophenol (560.5 g / 5.000 mol) dissolved in toluene (2.5 L) was added over 2.5 hours through an addition funnel. The reaction mixture was heated to reflux (100 ° C.) for 1 hour. A solution of 3-methoxybenzyl chloride (783.0 g / 5.000 mol) dissolved in toluene (750 mL) was added via addition funnel with reflux. After refluxing for 15 hours, the mixture was cooled to room temperature and added to H ₂ O (2.5 L). After stirring for 20 minutes, the layers were separated and the organic layer was extracted with a potassium hydroxide (720 g) solution (2.5 L) in MeOH. The MeOH layer was added to 20% aqueous potassium hydroxide solution and the mixture was stirred for 30 minutes. This mixture was then washed five times with toluene. Toluene washes were extracted with 20% aqueous KOH. All 20% aqueous KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl ether, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear colorless oil (449.0 g / 39% yield). bp: 120-130 degreeC / 50 mtorrHg. ¹ H NMR and MS [(M + H) ⁺ = 233] confirmed the target compound.

Step 2

A 12 liter three necked round bottom flask was equipped with a mechanical stirrer and N ₂ gas adapter. This system was purified with N ₂ . 4-fluoro-2- (3-methoxybenzyl) phenol (455.5 g / 1.961 mol) and dimethylformamide were added. The solution was cooled to 6 ° C. and sodium hydride (55.5 g / 2.197 mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g / 1.961 mol) was added. After 15 h, the reaction mixture was added to H ₂ O (4.0 L) and extracted twice with ethyl ether. The organic layers were combined, washed with saturated aqueous H ₂ O and NaCl, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the product (605.3 g, 97% yield). ¹ H NMR and MS [(M + H) ⁺ = 320] confirmed the target structure.

Step 3

A 12 liter round bottom flask was equipped with an N ₂ gas adapter, mechanical stirrer and reflux condenser. This system was purified with N ₂ . 4-Fluoro-2- (3-methoxybenzyl) -phenyldimethylthiocarbamate (605.3 g / 1.895 mol) and phenyl ether (2.0 kg) were added and the solution was heated to reflux for 2 hours. The mixture was stirred at rt for 64 h and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added and the resulting solution was stirred for 15 h. Potassium hydroxide (425.9 g / 7.590 mol) was added and the mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was concentrated by rotary evaporation, then dissolved in ethyl ether (1.0 L) and extracted with H ₂ O. The aqueous extracts were combined, acidified with concentrated HCl and extracted with ethyl ether. The ether extract was dried (MgSO ₄ ), filtered and concentrated in vacuo to give amber oil (463.0 g, 98% yield). ¹ H NMR confirmed the target structure.

Step 4

The 5-liter three-neck round bottom flask was equipped with an N ₂ gas adapter and a mechanical stirrer. This system was purified with N ₂ . 4-fluoro-2- (3-methoxybenzyl) -thiophenol (100.0 g / 403.2 mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 ° C. Sodium hydride (9.68 g / 383.2 mmol) was added slowly and the mixture was allowed to warm to room temperature. 2,2-dibutylpropylene sulfate (110.89 g / 443.6 mmol) was added and the mixture was stirred for 64 hours. The reaction mixture was concentrated by rotary evaporation and dissolved in H ₂ O. This aqueous solution was washed with ethyl ether and concentrated H ₂ SO ₄ was added. The aqueous solution was heated to reflux for 30 minutes, cooled to room temperature and extracted with ethyl ether. The ether solution was dried (MgSO ₄ ), filtered and concentrated in vacuo to give an amber oil (143.94 g / 85% yield). ¹ H NMR and MS [(M + H) ⁺ = 419] confirmed the target structure.

Step 5

A 2-liter four-necked round bottom flask was equipped with an N ₂ gas adapter and a mechanical stirrer. This system was clarified with N ₂ . The corresponding alcohol (143.94 g / 343.8 mmol) and CH ₂ Cl ₂ (1.0 L) were added and cooled to 0 ° C. Pyridinium chlorochromate (140.53 g / 651.6 mmol) was added. After 6 hours, CH ₂ Cl ₂ was added. After 20 minutes, the mixture was filtered through silica gel, washing with CH ₂ Cl ₂ . The filtrate was concentrated in vacuo to give a dark red oil (110.6 g, 77% yield). ¹ H NMR and MS [(M + H) ⁺ = 417] confirmed the target structure.

Step 6

A 2-liter four-necked round bottom flask was equipped with an N ₂ gas adapter and a mechanical stirrer. This system was purified with N ₂ . The corresponding sulfide (110.6 g / 265.5 mmol) and CH ₂ Cl ₂ (1.0 L) were added. The solution was cooled to 0 ° C. and 3-chloroperbenzoic acid (158.21 g / 531.7 mmol) was added in portions. After 30 minutes, the reaction mixture was warmed to room temperature. After 3.5 hours, the reaction mixture was cooled to 0 ° C. and filtered through a fine melt funnel. The filtrate was washed with 10% K ₂ CO ₃ aqueous solution. The emulsion formed was extracted with ethyl ether. The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the product (93.2 g, 78% yield). ¹ H NMR confirmed the target structure.

Step 7

A two liter four neck round bottom flask was equipped with an N ₂ gas adapter, a mechanical stirrer and a powder addition funnel. This system was purified with N ₂ . Corresponding aldehyde (93.2 g / 208 mmol) and THF (1.0 L) were added and the mixture was cooled to 0 ° C. Potassium tert-butoxide (23.35 g / 208.1 mmol) was added via an addition funnel. After 1 hour, 10% aqueous HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by recrystallization from 80/20 hexanes / ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene / ethyl acetate to give a white solid (33.60 g / total yield: 71%). ¹ H NMR confirmed the desired product.

Step 8

The Fisher Potter bottle was equipped with an N ₂ tube and a magnetic stirrer. This system was purified with N ₂ . The corresponding fluoro compound (28.1 g / 62.6 mmol) was added and the vessel sealed and cooled to -78 ° C. Dimethylamine (17.1 g / 379 mmol) was concentrated in a CO ₂ / acetone bath and added to the reaction vessel. This mixture was warmed to room temperature and heated to 60 ° C. After 20 hours, the reaction mixture was cooled down and dissolved in ethyl ether. The ether solution was washed with H ₂ O, saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a white solid (28.5 g / 96% yield). ¹ H NMR confirmed the target structure.

Step 9

A 250 ml three necked round bottom flask was equipped with an N ₂ gas adapter and a magnetic stirrer. This system was purified with N ₂ . The corresponding methoxy compound (6.62 g / 14.0 mmol) and CHCl ₃ were added. The reaction mixture was cooled to -78 ° C and boron tribromide (10.50 g / 41.9 mmol) was added. This mixture was allowed to warm to room temperature. After 4 hours, the reaction mixture was cooled to 0 ° C. and quenched with 10% K ₂ CO ₃ (100 mL). After 10 minutes, the layers were separated and the aqueous layer was extracted twice with ethyl ether. CHCl ₃ and ether extracts were combined, washed with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the product (6.27 g / 98% yield). ¹ H NMR confirmed the target structure.

Step 10

In a 250 ml one-neck round bottom flask equipped with a stirring rod, 2-diethylamineethyl chloride hydochloride (fw 172.10 g / mol), Aldrich D8, 720-1 (2.4 mmol, 4.12 g), 34 mL of anhydrous ether and 1N 34 mL KOH (aq) was added. After stirring for 15 minutes, it was separated by ether extraction and dried over anhydrous potassium carbonate.

To a separate two-neck 250 ml round bottom flask equipped with a stir bar was added sodium hydride (60% dispersion in mineral oil, 100 mg, 2.6 mmol) and 34 ml DMF. Cool to ice temperature. Next, 1.1 g (2.4 mmol) of the phenol product (preliminary product) in 5 mL of DMF and an ether solution prepared above were added. Heated to 40 ° C. for 3 days. The product, which confirmed the consumption of starting material by TLC, was diluted with ether, extracted with 5% NaOH batch, and then with water and then brine. The ether layer was dried over magnesium sulfate and separated by evaporation of the ether by rotary evaporation (1.3 g). The product can be further purified by chromatography (SiO ₂ 99% ethyl acetate / 1% NH ₄ OH, 5 mL / min) Separation yield: 0.78 g (mass spectrum and ¹ H NMR).

Step 11

The product obtained in step 10 (0.57 g, 1.02 mmol, fw 558.83 g / mol) and 1.6 g (10.02 mmol) of iodoethane were added to 5 ml of acetonitrile in the Fisher Potter bottle and heated at 45 ° C. for 3 days. It was. The solution was evaporated to dryness and redissolved in 5 ml of chloroform. To this chloroform solution, ether was then added and the resulting mixture was cooled. The desired product was isolated as a precipitate (0.7272 g). (Mass spectrum MI = 587.9, ¹ H NMR).

Example 1401

Step 1

A 12 liter, four necked round bottom flask was equipped with a reflux condenser, N ₂ gas adapter, mechanical stirrer and addition funnel. This system was purified with N ₂ . A slurry in which sodium hydride (126.0 g / 4.988 mol) was dispersed in toluene (2.5 L) was added, and the mixture was cooled to 6 ° C. A solution of 4-fluorophenol (560.5 g / 5.000 mol) dissolved in toluene (2.5 L) was added over 2.5 hours through an addition funnel. The reaction mixture was heated to reflux (100 ° C.) for 1 hour. A solution of 3-methoxybenzyl chloride (783.0 g / 5.000 mol) dissolved in toluene (750 mL) was added via addition funnel with reflux. After refluxing for 15 hours, the mixture was cooled to room temperature and added to H ₂ O (2.5 L). After stirring for 20 minutes, the layers were separated and the organic layer was extracted with a potassium hydroxide (720 g) solution (2.5 L) in MeOH. The MeOH layer was added to 20% aqueous potassium hydroxide solution and the mixture was stirred for 30 minutes. This mixture was then washed five times with toluene. Toluene washes were extracted with 20% aqueous KOH. All 20% aqueous KOH solutions were combined and acidified with concentrated HCl. The acidic solution was extracted three times with ethyl ether, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by Kugelrohr distillation to give a clear colorless oil (449.0 g / 39% yield). bp: 120-130 degreeC / 50 mtorrHg. ¹ H NMR and MS [(M + H) ⁺ = 233] confirmed the target compound.

Step 2

A 12 liter three necked round bottom flask was equipped with a mechanical stirrer and N ₂ gas adapter. This system was purified with N ₂ . 4-fluoro-2- (3-methoxybenzyl) phenol (455.5 g / 1.961 mol) and dimethylformamide were added. The solution was cooled to 6 ° C. and sodium hydride (55.5 g / 2.197 mol) was added slowly. After warming to room temperature, dimethylthiocarbamoyl chloride (242.4 g / 1.961 mol) was added. After 15 h, the reaction mixture was added to H ₂ O (4.0 L) and extracted twice with ethyl ether. The organic layers were combined, washed with H ₂ O and saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the product (605.3 g, 97% yield). ¹ H NMR and MS [(M + H) ⁺ = 320] confirmed the target structure.

Step 3

A 12 liter round bottom flask was equipped with an N ₂ gas adapter, mechanical stirrer and reflux condenser. This system was purified with N ₂ . 4-Fluoro-2- (3-methoxybenzyl) -phenyldimethylthiocarbamate (605.3 g / 1.895 mol) and phenyl ether (2.0 kg) were added and the solution was heated to reflux for 2 hours. The mixture was stirred at rt for 64 h and then heated to reflux for 2 h. After cooling to room temperature, MeOH (2.0 L) and THF (2.0 L) were added and the resulting solution was stirred for 15 h. Potassium hydroxide (425.9 g / 7.590 mol) was added and the mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was concentrated by rotary evaporation, then dissolved in ethyl ether (1.0 L) and extracted with H ₂ O. The aqueous extracts were combined, acidified with concentrated HCl and extracted with ethyl ether. The ether extract was dried (MgSO ₄ ), filtered and concentrated in vacuo to give an amber oil (463.0 g, 98% yield). ¹ H NMR confirmed the target structure.

Step 4

The 5-liter three-neck round bottom flask was equipped with an N ₂ gas adapter and a mechanical stirrer. This system was purified with N ₂ . 4-fluoro-2- (3-methoxybenzyl) -thiophenol (100.0 g / 403.2 mmol) and 2-methoxyethyl ether (1.0 L) were added and the solution was cooled to 0 ° C. Sodium hydride (9.68 g / 383.2 mmol) was added slowly and the mixture was allowed to warm to room temperature. 2,2-dibutylpropylene sulfate (110.89 g / 443.6 mmol) was added and the mixture was stirred for 64 hours. The reaction mixture was concentrated by rotary evaporation and dissolved in H ₂ O. This aqueous solution was washed with ethyl ether and concentrated H ₂ SO ₄ was added. The aqueous solution was heated to reflux for 30 minutes, cooled to room temperature and extracted with ethyl ether. The ether solution was dried (MgSO ₄ ), filtered and concentrated in vacuo to give an amber oil (143.94 g / 85% yield). ¹ H NMR and MS [(M + H) ⁺ = 419] confirmed the target structure.

Step 5

A 2-liter four-necked round bottom flask was equipped with an N ₂ gas adapter and a mechanical stirrer. This system was clarified with N ₂ . The corresponding alcohol (143.94 g / 343.8 mmol) and CH ₂ Cl ₂ (1.0 L) were added and cooled to 0 ° C. Pyridinium chlorochromate (140.53 g / 651.6 mmol) was added. After 6 hours, CH ₂ Cl ₂ was added. After 20 minutes, the mixture was filtered through silica gel, washing with CH ₂ Cl ₂ . The filtrate was concentrated in vacuo to give a dark red oil (110.6 g, 77% yield). ¹ H NMR and MS [(M + H) ⁺ = 417] confirmed the target structure.

Step 6

A 2-liter four-necked round bottom flask was equipped with an N ₂ gas adapter and a mechanical stirrer. This system was purified with N ₂ . The corresponding sulfide (110.6 g / 265.5 mmol) and CH ₂ Cl ₂ (1.0 L) were added. The solution was cooled to 0 ° C. and 3-chloroperbenzoic acid (158.21 g / 531.7 mmol) was added in portions. After 30 minutes, the reaction mixture was warmed to room temperature. After 3.5 hours, the reaction mixture was cooled to 0 ° C. and filtered through a fine melt funnel. The filtrate was washed with 10% K ₂ CO ₃ aqueous solution. The emulsion formed was extracted with ethyl ether. The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the product (93.2 g, 78% yield). ¹ H NMR confirmed the target structure.

Step 7

A two liter four neck round bottom flask was equipped with an N ₂ gas adapter, a mechanical stirrer and a powder addition funnel. This system was purified with N ₂ . Corresponding aldehyde (93.2 g / 208 mmol) and THF (1.0 L) were added and the mixture was cooled to 0 ° C. Potassium tert-butoxide (23.35 g / 208.1 mmol) was added via an addition funnel. After 1 hour, 10% aqueous HCl (1.0 L) was added. After 1 h, the mixture was extracted three times with ethyl ether, dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by recrystallization from 80/20 hexanes / ethyl acetate to give a white solid (32.18 g). The mother liquor was concentrated in vacuo and recrystallized from 95/5 toluene / ethyl acetate to give a white solid (33.60 g / total yield: 71%). ¹ H NMR confirmed the desired product.

Step 8

The Fisher Potter bottle was equipped with an N ₂ tube and a magnetic stirrer. This system was purified with N ₂ . The corresponding fluoro compound (28.1 g / 62.6 mmol) was added and the vessel sealed and cooled to -78 ° C. Dimethylamine (17.1 g / 379 mmol) was concentrated in a CO ₂ / acetone bath and added to the reaction vessel. This mixture was warmed to room temperature and heated to 60 ° C. After 20 hours, the reaction mixture was cooled down and dissolved in ethyl ether. The ether solution was washed with H ₂ O, saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a white solid (28.5 g / 96% yield). ¹ H NMR confirmed the target structure.

Step 9

A 250 ml three necked round bottom flask was equipped with an N ₂ gas adapter and a magnetic stirrer. This system was purified with N ₂ . The corresponding methoxy compound (6.62 g / 14.0 mmol) and CHCl ₃ were added. The reaction mixture was cooled to -78 ° C and boron tribromide (10.50 g / 41.9 mmol) was added. This mixture was allowed to warm to room temperature. After 4 hours, the reaction mixture was cooled to 0 ° C. and quenched with 10% K ₂ CO ₃ (100 mL). After 10 minutes, the layers were separated and the aqueous layer was extracted twice with ethyl ether. CHCl ₃ and ether extracts were combined, washed with saturated aqueous NaCl solution, dried (MgSO ₄ ), filtered and concentrated in vacuo to afford the product (6.27 g / 98% yield). ¹ H NMR confirmed the target structure.

Step 10

In a 250 ml one-neck round bottom flask equipped with a stirring rod, 2-diethylamineethyl chloride hydochloride (fw 172.10 g / mol), Aldrich D8, 720-1 (2.4 mmol, 4.12 g), 34 mL of anhydrous ether and 1N 34 mL KOH (aq) was added. After stirring for 15 minutes, it was separated by ether extraction and dried over anhydrous potassium carbonate.

To a separate two-neck 250 ml round bottom flask equipped with a stir bar was added sodium hydride (60% dispersion in mineral oil, 100 mg, 2.6 mmol) and 34 ml DMF. Cool to ice temperature. Next, 1.1 g (2.4 mmol) of the phenol product (preliminary product) in 5 mL of DMF and an ether solution prepared above were added. Heated to 40 ° C. for 3 days. The product, which confirmed the consumption of starting material by TLC, was diluted with ether, extracted with 5% NaOH batch, and then with water and then brine. The ether layer was dried over magnesium sulfate and separated by rotary evaporation to remove the ether (1.3 g). The product can be further purified by chromatography (SiO ₂ 99% ethyl acetate / 1% NH ₄ OH, 5 mL / min) Separation yield: 0.78 g (mass spectrum and ¹ H NMR).

Step 11

The product obtained in step 10 (0.57 g, 1.02 mmol, fw 558.83 g / mol) and 1.6 g (10.02 mmol) of iodoethane were added to 5 ml of acetonitrile in the Fisher Potter bottle and heated to 45 ° C. for 3 days. It was. The solution was evaporated to dryness and redissolved in 5 ml of chloroform. To this chloroform solution, ether was then added and the resulting mixture was cooled. The desired product was isolated as a precipitate (0.7272 g). (Mass spectrum MI = 587.9, ¹ H NMR).

Example 1402

(4R-cis) -5-[[5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1- Dioxido-1-benzothiepin-5-yl] phenoxy] pentyl] thio] -1 H-tetrazol-1-acetic acid

Step 1. Preparation of 4-fluoro-2-((4-methoxyphenyl) methyl) -phenol

100.0 g of 4-fluorophenol (0.89 mol) was added at 0 ° C to a solution in which 23.66 g of 95% sodium hydride (0.94 mol) was stirred and dissolved in 600 ml of anhydrous toluene. The mixture was stirred at 90 ° C. for 1 hour until gas evolution ceased. The mixture was cooled to room temperature and a solution in which 139.71 g of 3-methoxybenzyl chloride (0.89 mol) was dissolved in 400 ml of anhydrous toluene was added. After refluxing for 24 hours, the mixture was cooled to room temperature and quenched with 500 mL of water. The organic layer was separated, dried over MgSO ₄ , and concentrated under high vacuum. Remaining starting material was distilled off. The crude dark red oil was filtered through 1 L silica gel layer with pure hexanes to give 53.00 g (25.6%) of the title product as a pink solid. ¹ H NMR (CDCl ₃ ) δ 3.79 (s, 3H), 3.90 (s, 2H), 4.58 (s, lH), 6.70-6.74 (m, lH), 6.79-6.88 (m, 4H), 7.11-7.16 (m, 2 H).

Step 2. Preparation of 4-fluoro-2-((4-methoxyphenyl) methyl) -thiophenol

Step 2a. Preparation of Thiocarbamates

11.20 g of 60% sodium hydride in mineral oil (279.90 mmol) was dissolved in a solution in which 50.00 g (215.30 mmol) of 4-fluoro-2-((4-methoxyphenyl) methyl) -phenol was stirred and dissolved in 500 mL of anhydrous DMF. Add at ° C. The mixture was warmed to room temperature and 26.61 g of dimethylthiocarbamoyl chloride (215.30 mmol) was added. The reaction mixture was stirred at rt overnight. The mixture was quenched with 100 ml of water in an ice bath. The solution was extracted with 500 mL diethyl ether. The ether solution was washed with 500 ml of water and 500 ml of brine. The ether solution was dried over MgSO ₄ and distilled off. The crude product was filtered through a 500 ml silica gel plug with 5% ethyl acetate / hexanes to give 48.00 g (69.8%) of the title product as a pale white solid. ¹ H NMR (CDCl ₃ ) δ3.21 (s, 3H), 3.46 (s, 3H), 3.80 (s, 3H), 3.82 (s, 2H), 6.78-6.86 (m, 3H), 6.90-7.00 ( m, 2H), 7.09 (d, J = 8.7 Hz, 2H).

Step 2b. Rearrangement and Hydrolysis of Thiocarbamate to 4-Fluoro-2-((4-methoxyphenyl) methyl) -thiophenol

A solution in which 48.00 g (150.29 mmol) of thiocarbamate (obtained in step 2a) was stirred and dissolved in 200 ml of diphenyl ether was refluxed at 270 ° C. overnight. The solution was cooled to room temperature and filtered through 1 L silica gel with 2 L of hexane to remove phenyl ether. The rearrangement product was washed with 5% ethyl acetate / hexanes to give 46.00 g (95.8%) product as a pale yellow solid. ¹ H NMR (CDCl ₃ ) δ3.02 (s, 3H), 3.10 (s, 3H), 3.80 (s, 3H), 4.07 (s, 2H), 6.82-6.86 (m, 3H), 6.93 (dt, J = 8.4 Hz, 2.7 Hz, lH), 7.08 (d, J = 8.7 Hz, 2H), 7.49 (dd, J = 6.0 Hz, 8.7 Hz, lH).

17.28 g (432.06 mmol) of NaOH was added to a solution of 46.00 g (144.02 mmol) of the rearrangement product in 200 mL of methanol and 200 mL of THF. This mixture was refluxed under nitrogen overnight. The solvent was evaporated off and 200 ml of water was added. The aqueous solution was washed twice with 200 ml of diethyl ether and placed in an ice bath. The aqueous mixture was acidified to pH 6 with HCl concentrated solution. This solution was extracted twice with 300 ml of diethyl ether. The ether layers were combined, dried over MgS0 ₄ and distilled off to give 27.00 g (75.5%) of the product as a brown oil. ¹ H NMR (CDC1 ₃ ) δ 3.24 (s, lH), 3.80 (s, 3H), 3.99 (s, 2H), 6.81-6.87 (m, 4H), 7.09 (d, J = 8.7 Hz, 2H), 7.27-7.33 (m, lH).

Step 3. Preparation of Dibutyl Cyclic Sulphate

Step 3a. Preparation of 2,2-dibutyl-1,3-propanediol

In acetone / dry ice bath, 662 mL (1.2 equiv., 0.66 mol) of LAH (1M THF) was dissolved in a solution in which dibutyl-diethylmalonate (Aldrich) (150 g, 0.55 mol) was stirred and dissolved in anhydrous THF (700 mL). Added dropwise. At this time, the reaction temperature was maintained at -20 to 0 ℃. The reaction was stirred at rt overnight. The reaction was then cooled to −20 ° C. and 40 mL of water, 80 mL of 10% NaOH and 80 mL of water were added dropwise. The resulting suspension was filtered. The filtrate was dried over sodium sulfate and concentrated in vacuo to give 98.4 g (95% yield) of diol as an oil. MS spectra and quantum NMR and carbon NMR spectra were consistent with the product.

Step 3b. Preparation of Dibutyl Cyclic Sulfite

A solution of 2,2-dibutyl-1,3-propanediol (103 g, 0.548 mol, obtained in step 3a) and triethylamine (221 g, 2.9 mol) in anhydrous methylene chloride (500 mL) was dissolved at 0 ° C. Stir under nitrogen. Thionyl chloride (97.8 g, 0.82 mol) was added dropwise to this mixture, and the solution yellowed within 5 minutes and then blacked when the addition was completed within 30 minutes. The reaction mixture was stirred at 0 ° C for 3 h. GC confirmed no starting material. The mixture was washed twice with ice water and then twice with brine. The organic phase was dried over magnesium sulfate and concentrated in vacuo to give 128 g (100%) of dibutyl cyclic sulfite as a black oil. Mass spectrum (MS) was consistent with the product.

Step 3c. Oxidation of dibutyl cyclic sulfite to dibutyl cyclic sulfate

Ruthenium (III) (1g) and iodide in a solution of dibutyl cyclic sulfite (127.5 g, 0.54 mol, obtained in step 3b) in 500 ml of water cooled in an ice bath and 600 ml of acetonitrile under nitrogen atmosphere Sodium acid (233 g, 1.08 mol) was added. After the reaction was stirred overnight, the color of the solution turned black. GC confirmed no starting material. The mixture was extracted with 300 ml of ether and the ether extract was washed three times with brine. The organic phase was dried over magnesium sulphate and passed through celite. The filtrate was concentrated in vacuo to give 133 g (97.8%) of dibutyl cyclic sulfate as an oil. Proton and carbon NMR and MS were consistent with the product.

Step 4. Preparation of Aryl-3-hydroxypropylsulfide

60% in mineral oil (108.73 mmol) in a solution in which 27.00 g (108.73 mmol) of 4-fluoro-2-((4-methoxyphenyl) methyl) thiophenol (obtained in step 2) was stirred and dissolved in 270 ml of diglyme 4.35 g of sodium hydride dispersion was added at 0 ° C. After gas evolution had ceased, 29.94 g (119.60 mmol) of dibutyl cyclic sulfate (obtained in step 3c) were added at 0 ° C. and stirred for 10 minutes. The mixture was allowed to warm up to room temperature and stirred overnight. The solvent was evaporated and 200 ml of water added. The solution was washed with 200 ml of diethyl ether, 25 ml of concentrated sulfuric acid was added to make a 2.0 M solution and refluxed overnight. This solution was extracted with ethyl acetate and the organic solution was dried over MgSO ₄ and concentrated in vacuo. The crude aryl-3-hydroxypropylsulfide was purified by silica gel chromatography (Waters Prep 500) using 8% ethyl acetate / hexanes to give 33.00 g (72.5%) of the product as a light brown oil. ¹ H NMR (CDCl ₃ ) δ 0.90 (t, J = 7.l Hz, 6H), 1.14-1.34 (m, 12H), 2.82 (s, 2H), 3.48 (s, 2H), 3.79 (s, 3H ), 4.10 (s, 2H), 6.77-6.92 (m, 4H), 7.09 (d, J = 8.7 Hz, 2H), 7.41 (dd, J = 8.7 Hz, 5.7 Hz, lH).

Step 5. Preparation of High Concentration of Aryl-3-hydroxypropylSulfoxide of Enantiomer

96% (1R)-(-)-(8,8-dichloro-10-campo) in a solution of 20.00 g (47.78 mmol) of aryl-3-hydroxypropylsulfide (obtained in step 4) in 1 L of methylene chloride was stirred and dissolved. 31.50 g (100.34 mmol, Aldrich) of sulfonyl) oxaziridine was added at 2 ° C. After all of the oxaziridine was dissolved, the mixture was left for 72 hours in a -30 ° C freezer. After evaporation of the solvent, the crude solid was washed with 1 L of hexane. The white solid was filtered off and the hexane solution was concentrated in vacuo. The crude oil was purified on silica gel column (Waters Prep 500) with 15% ethyl acetate / hexanes to give 19.00 g (95%) of aryl-3-hydroxypropylsulfoxide with high enantiomer concentration as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 0.82-0.98 (m, 6H), 1.16-1.32 (m, 12H), 2.29 (d, J = l3.8 Hz, lH), 2.77 (d, J = 13.5 Hz, lH ), 3.45 (d, J = 12.3 Hz, lH), 3.69 (d, J = 12.3 Hz, lH), 3.79 (s, 3H), 4.02 (q, J = 15.6 Hz, 1H), 6.83-6.93 (m , 3H), 7.00 (d, J = 8.l Hz, 2H), 7.18--7.23 (m, lH), 7.99-8.04 (m, lH). Enantiomeric excess was determined by chiral HPLC on a (R, R) -Whelk-O column using 5% ethanol / hexane as eluent. As a result, the first elution peak was found to be 78% ee as the main product.

Step 6. Preparation of High Concentration of Aryl-3-Propanalsulfoxide

19.00 g (43.72 mmol) of aryl-3-hydroxypropylsulfoxide (obtained in step 5) having a high enantiomer concentration in a solution of 13.27 g of triethylamine (131.16 mmol, Aldrich) was stirred and dissolved in 200 ml of dimethyl sulfoxide. 20.96 g (131.16 mmol, Aldrich) of sulfur trioxide-pyridine was added at room temperature. The mixture was stirred at rt for 48 h, then 500 mL of water was added and vigorously stirred. This mixture was extracted twice with 500 ml of ethyl acetate. The ethyl acetate layer was separated, dried over MgSO ₄ and concentrated in vacuo. The crude oil was filtered through 15% ethyl acetate / hexane through 500 ml of silica gel to obtain 17.30 g (91%) of aryl-3-propanalsulfoxide having a high enantiomer concentration in light orange oil. ¹ H NMR (CDC1 ₃ ) δ 0.85- 0.95 (m, 6H), 1.11-1.17 (m, 4H), 1.2ll.39 (m, 4H), 1.59-1.76 (m, 4H), 1.89-1.99 (m, lH), 2.57 (d, J = l4.l Hz, lH), 2.9l (d, J = 13.8 Hz, lH), 3.79 (s, 3H), 3.97 (d, J = 15.9 HZ, lH ), 4,12 (d, J = 15.9 Hz, lH), 6.84-6.89 (m, 3H), 7.03 (d, J = 8.4 Hz, 2H) 7.19 (dt, J = 8.4 Hz, 2.4 Hz, 1H) , 8.02 (dd, J = 8.7 Hz, 5.7 Hz, lH), 9.49 (s, lH).

Step 7. Preparation of Tetrahydrobenzothiene-1-oxide (4R, 5R) with High Enantiomer Concentration

1.0 M t-butoxide (1.2 equivalents) of THM in THF was dissolved in 300 ml of anhydrous THF with 17.30 g (39.99 mmol) of high concentration of the enantiomer obtained in step 6 at 300 mL of dry THF. 48 ml) was added under nitrogen atmosphere. This solution was stirred at -15 ° C for 4 h. Then, the reaction was quenched with 100 mL of water and neutralized with 4 mL of HCl concentrated solution at 0 ° C. The THF layer was separated, dried over MgSO ₄ and concentrated in vacuo. Tetrahydrobenzothiefine-1-oxide (4R, 5R) with high enantiomer concentration was purified by silica gel chromatography (Waters Prep 500) using 15% ethyl acetate / hexanes to give 13.44 g (77.7%) of the product as a white solid. Obtained as. ¹ H NMR (CDC1 ₃ ) δ 0.87-0.97 (m, 6H), 1.16-1.32 (m, 4H), 1.34-1.48 (m, 4H), 1.50-1.69 (m, 4H), 1.86- 1.96 (m, 1H), 2.88 (d, J = 13.0 H, 1H), 3.00 (d, J = 13.0 H, 1H), 3.85 (s, 3H), 4.00 (s, 1H), 4.48 (s, 1H ), 6.52 (dd, J = 9.9 Hz, 2.4 Hz, 1H), 6.94 (d, J = 9 Hz, 2H), 7.13 (dt, J = 8.4 Hz, 2.4 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.82 (dd, J = 8.7 Hz, 5.7 Hz, 1H).

Step 8. Preparation of Tetrahydrobenzothiene-1,1-Dioxide (4R, 5R) with Enantiomers at High Concentration.

68% m-chloroperoxybenzoic acid (37.28 mmol, sigma) in a solution of 13.44 g (31.07 mmol) of tetrahydrobenzothiene-1-oxide having a high concentration of enantiomer obtained in step 7 was stirred and dissolved in 150 ml of methylene chloride. g was added at 0 ° C. After 2 hours of stirring at 0 ° C., the mixture was warmed to room temperature and stirred for 4 hours. To this mixture was added 50 ml of saturated Na ₂ SO ₃ and stirred for 30 minutes. This solution was then neutralized with 50 mL of saturated NaHCO ₃ solution. The methylene chloride layer was separated, dried over MgSO ₄ , and concentrated in vacuo to give 13.00 g (97.5%) of tetrahydrobenzothiene-1,1-dioxide (4R, 5R), the high concentration of the title enantiomer. Obtained as. ¹ H NMR (CDC1 ₃ ) δ 0.89-0.95 (m, 6H), 1.09-1.42 (m, 12H), 2.16-2.26 (m, 1H), 3.14 (q, J = 15.6 Hz, lH), 3.87 (s , 3H), 4.l8 (s. 1H), 5.48 (s, lH), 6.54 (dd, J = 10.2 Hz, 2.4 Hz, lH), 6.96-.7.07 (m, 3H), .7.40 (d, J = 8.l Hz, 2H), 8.11 (dd, J = 8.6 Hz, 5.9 Hz, 1H).

Step 9. Preparation of 7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (4R, 5R) with high concentration of enantiomers

In the Parr reactor, pure dimethyl is dissolved in 73 ml of dimethylamine (2.0 M in THF, 146 mmol) in 13.00 g (28.98 mmol) of high concentrations of tetrahydrobenzothiene-1,1-dioxide in the enantiomer obtained in step 8 About 20 mL of amine was added. The mixture was sealed and stirred at 110 ° C. overnight, then cooled to room temperature. Excess dimethylamine was evaporated. The crude oil was dissolved in 200 ml of ethyl acetate, washed with 100 ml of water, dried over MgSO ₄ and concentrated in vacuo. Purification using 20% ethyl acetate / hexanes on a silica gel column (Waters Prep 500) showed 7- (dimethylamine) tetrahydrobenzothiene-1,1-dioxide (4R, 5R) in high concentrations of the enantiomer of the title. 12.43 g (90.5%) was obtained as a colorless solid. ¹ H NMR (CDC1 ₃ ) δ 0.87-0.93 (m, 6H), 1.10-1.68 (m, 12H), 2.17-2.25 (m, lH), 2.8l (s, 6H), 2.99 (d, J = l5 .3 Hz, lH), 3.15 (d, J = 15.3 HZ, lH), 3.84 (S, 3H), 4.11 (d, J = 7.5 HZ, lH), 5.49 (s, lH), 5.99 (d, J = 2.4 Hz, lH), 6.51 (dd, J = 8.7 Hz, 2.4 Hz, lH), 6.94 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.7 Hz, lH). The product was found to be 78% ee by chiral HPLC using 5% ethanol / hexane as eluent on a Chiralpak AD column. This solid was recrystallized from ethyl acetate / hexanes to give 1.70 g of racemic product. The remaining solution was concentrated and recrystallized to give 9.8 g of a colorless solid. Enantiomeric excess of this solid was determined by chiral HPLC using 5% ethanol / hexane as eluent on a Chiral AD column. As a result, it was confirmed that the first elution peak was 96% ee as the main product.

Step 10: Demethylation of 5- (4'-methoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (4R, 5R)

In a solution obtained by dissolving 47 g (99 mmol) of (dimethylamino) tetrahydrobenzothiene-1,1-dioxide having high concentration of the enantiomer obtained in step 9 in 50 ml of methylene chloride at -10 ° C, boron tribromide solution (297 ml, 1 M solution in methylene chloride, 297 mmol) was added dropwise, and the resulting solution was stirred at low temperature (-5 ° C to 0 ° C) for 1 hour or until completion of reaction. The reaction was cooled to −10 ° C. in an acetone-dry ice bath and slowly quenched with 300 mL of water. The mixture was warmed to 10 ° C. and then diluted further with 300 ml of saturated sodium bicarbonate solution to neutralize the mixture. The aqueous layer was separated and extracted with 300 ml of methylene chloride, then the combined extracts were washed with 200 ml of water, brine, dried over MgSO ₄ and concentrated in vacuo. The residue was dissolved in 500 ml of ethyl acetate and 500 ml of glacial acetic acid was added and stirred at room temperature for 30 minutes. The mixture was washed twice with 200 ml of water and 200 ml of brine, dried over MgSO ₄ and concentrated in vacuo to afford crude 4-hydroxyphenyl intermediate. The solid residue was recrystallized from methylene chloride to give 37.5 g (82%) of the desired 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide as a white solid. . ¹ H NMR (CDC1 ₃ ) δ 0.84-0.97 (m, 6H), 1.1-1.5 (m, 10H), 1.57-1.72 (m, lH), 2.14-2.28 (m, lH), 2.83 (s, 6H) , 3.00 (d, J = 15.3 Hz, lH), 3.16 (d, J = 15.3 Hz, lH), 4.11 (s, 2H), 5.48 (s, lH), 6.02 (d, J = 2.4 Hz, lH) , 6.55 (dd, J = 9, 2.4 Hz, lH), 6.88 (d, 8,7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 7.91 (d, J = 9 Hz, 2H) .

Alternatively, 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide having a high concentration of the enantiomer described above as an intermediate is chiral after non-enantioselective synthesis. It can be prepared by chromatographic separation. Aryl-3-hydroxypropylsulfide (obtained in step 4) was oxidized to m-chloroperbenzoic acid (performed under similar conditions as in step 8 except using 2.2 equivalents of m-CPBA) to obtain racemic sulfone intermediates. This sulfone was run through a synthetic sequence to yield racemic 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide. These two enantiomers were further converted to 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide with high concentrations of the desired enantiomers by appropriate chiral chromatography purification. Separated.

Step 11: Preparation of Ester Intermediates

95% in a solution of 1.0 g (2.18 mmol) of 5- (4'-hydroxyphenyl) -7-dimethylamino) tetrahydrobenzothiefine-1,1-dioxide obtained in step 10 in 10 ml of dimethylformamide 60 mg (2.38 mmol) of sodium hydride was added and stirred for 15 minutes. 400 µl (2.52 mmol) of benzyl 2-bromoacetate was added to the reaction mixture and stirred for 2 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and solvent evaporated to afford 1.30 g (98%) of the title ester intermediate. ¹ H NMR (CDCl ₃ ) δ 0.88-0.94 (m, 6H), 1.13-1.46 (m, 10H), 1.60-1.64 (m, lH), 2.20-2.24 (m, lH), 2.81 (s, 6H) , 3.00 (d, J = 15.lHz, lH), 3.16 (t, J = 15.l Hz, lH), 4.11 (s, lH), 5.26 (s, 2H), 5.49 (s, lH), 6.04 (d, J = 2.4 Hz, lH), 6.63 (dd, J = 8.9, 2.4 Hz, lH), 6.95 (d, J = 8.7 Hz, 2H) 7.37 (s, 5H), 7.42 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.9 Hz, lH).

Step 12: Preparation of Acid

The solution in which 1.30 g (2.14 mmol) of the ester intermediate obtained in step 11 was dissolved in 40 ml of ethanol was maintained with hydrogen gas atmosphere (40 psi) with 10% palladium on carbon for 3 hours. The reaction mixture was filtered through celite and the solvent was evaporated to afford the desired title compound as a white solid. mp. 119-l23 deg. ¹ H NMR (CDCl ₃ ) δ 0.89-0.94 (m, 6H), l.19-1.43 (m, lH), 1.61-1.65 (m, lH), 2.17-2.21 (m, lH), 2.85 (s. 6H), 3.02 (d, J = 15.l HZ, lH), 3.17 (t, J = 14.9 Hz, lH), 4.12 (s, 1H), 4.72 (s, 2H), 5.5l (s, lH) , 6.17 (s, lH), 6.74 (d, J = 9.l Hz, lH), 6.99 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.7 Hz, lH). HRMS. Calcd for C ₂₈ H ₄₀ NO ₆ S: 518.2576. Found: 518.2599.

Example 1403

(4R-cis) -5-[[5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1- Dioxido-1-benzothiepin-5-yl] phenoxy] pentyl] thio] -1 H-tetrazol-1-acetic acid

Step 1: Preparation of Glycine Ester Intermediates

Example 1402 6.4 g (13.9 mmol) of 5- (4′-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide obtained in step 10 and 2.9 g (21.0 mmol) of potassium carbonate To 3.8 g (21.0 mmol) of N- (chloroacetyl) glycine ethyl ester and 50 mg (0.14 mmol) of tetrabutylammonium iodide were added to the solution dissolved in 100 ml of acetone. The reaction was heated to reflux for 2 days, cooled to room temperature, stirred for 20 hours, and then fractionated with ethyl acetate and water. The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo. Silicagel chromatography (Waters Prep-500) purification using 50% ethyl acetate / hexanes yielded 7.5 g (90%) of glycine ester intermediate as a white foam. ¹ H NMR (CDCl ₃ ) δ 0.86-0.98 (m, 6H), 1.04-1.56 (m, 13H), 1.58-1.71 (m, lH), 2.14-2.29 (m, lH), 2.73 (s, 6H) , 3.08 (AB _q , J _AB = 15.3 HZ, J = 48.9 HZ, 2H), 4.06-4.19 (m, 6H), 4.25 (q, J = 7.0 Hz, 2H), 4.57 (s, 2H), 5.50 ( s, lH), 5.98 (s, lH), 6.56 (d, J = 8.6 Hz, lH), 6.98 (d, J = 8.5 Hz, 2H), 7.l7 (s, lH), 7.47 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.7 Hz, lH).

Step 2: Preparation of Acid

A solution of 7.3 g (12.1 mmol) of glycine ester intermediate obtained in step 1 and 1.5 g (36.3 mmol) of LiOH.H ₂ O was dissolved in 60 mL of THF and 60 mL of water was heated to 45 ° C. for 2 hours. The solution was then cooled to room temperature, acidified with 1N HCl and fractionated with ethyl acetate and water. The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo. Purification by recrystallization from ethyl acetate gave 5.45 g (78%) of the title compound as a white crystalline solid. mp. 149-150 ° C .; ¹ H NMR (CD ₃ OD) δ 0.88-O.98 (m, 6H), 1.06-1.56 (m, 10H), 1.70-1.84 (m, lH), 2.06-2.20 (m, lH), 2.79 (S , 6H), 3.l1 (AB _q , J _AB = 15.3 HZ, J = 21.6 Hz, 2H), 4.01 (s, 2H), 4.07 (s, lH), 4.61 (s, 2H), 5.3l (s , lH), 6.04 (s, lH), 6.57 (d, J = 9.0 Hz, lH), 7.08 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 8.l Hz. 2H), 7.76 (d, J = 9.0 Hz, lH), 8.42 (m, lH). HRMS (ES &lt; + &gt;) Calcd for C ₃₀ H ₄₂ N ₂ 0 ₇ S: 575. 2712. Found: 575. 2 7 g 0.

Elemental Analysis for C ₃₀ H ₄₂ N ₂ O ₇ S

Calculated: C, 62.69; H, 7. 37; N, 4.87.

Found: C, 62.87; H, 7.56; N, 4.87.

Example 1404

(4R-cis) -5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido- 1-benzothiepin-5-yl] phenoxy] pentanoic acid

Step 1: Preparation of Ester Intermediates

Example 1402, 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (1.0 g, 2.2 mmol) obtained in step 10 was added to acetone (10 mL). The solution dissolved under N ₂ at 25 ° C. was dissolved in K ₂ CO ₃ powder (0.45 g, 3.3 mmol, 1.5 equiv), benzyl 5-bromovalericate (0.88 g, 3.3 mmol, 1.5 equiv) and catalytic amount of iodide tetra-n Treated with butylammonium (2 mg) and the resulting solution was stirred at 65 ° C. for 24 h. The pale amber slurry was cooled to 25 ° C. and concentrated in vacuo to afford a yellow residue. Purification by flash chromatography (2.4 × 30 cm silica, 20-40% EtOAc / hexanes) afforded the ester intermediate (1.2 g, 86%) as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 0.91 (m, 6H), l.11-1.47 (br m, 1OH), 1.64 (m, 1H), 1.86 (m, 2H), 2.21 (m, lH), 2.47 ( m, 2H), 2.81 (s.6H), 3.05 (ABq, J-15.l Hz, J = 47.7 Hz, 2H), 4.10 (d, J = 7.9 Hz, lH), 5.13 (s, 2H), 5.47 (s, lH), 6.00 (d, J = 2.5 Hz, lH), 6.50 (dd, J = 8.9, 2.5 Hz, lH), 6.91 (d, J = 8.7 Hz, 2H), 7.36 (m, 5H ), 7.40 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.9 Hz, lH); HRMS. Calcd for C ₃₈ H ₅₁ NO ₆ S: 650.3515. Found: 650.3473.

Step 2: Preparation of Acid

The solution of the ester intermediate obtained in step 1 (0.99 g, 1.5 mmol) dissolved in ethanol (7.5 ml) at 25 ° C. was treated with 5% palladium on carbon (0.15 g, 10 wt%) and then H Stir under ₂ atmosphere (1 atm). Hydrogen gas was injected through the slurry for 1 minute every 10 minutes for a total reaction time of 4 hours. This slurry was placed under N ₂ atmosphere and nitrogen was injected for 10 minutes through the reaction mixture. This mixture was filtered through a plug of Celite® (10 g) and concentrated in vacuo to give a white foam. Flash chromatography (2.6 × 25 cm silica, 1.5% EtOH / CH ₂ Cl ₂ ) purified to afford the desired title compound (0.54 g, 63%) as a white foam. mp: 76-79 ° C .. ¹ H NMR (CDC1 ₃ ) δ 0.90 (m, 6H), 1.10-1.46 (br m, 10H), 1.62 (m, lH), 1.87 (m, 4H), 2.20 (m, lH), 2.45 (m, 2H), 2.81 (s, 6H), 3.05 (ABq, J = 15.l Hz, J = 49.7 Hz, 2H), 4.00 (s, 2H), 4.09 (s, lH), 5.45 (S, lH), 5.99 (d, J = 2.4 Hz, lH), 6.48 (dd, J = 8.9, 2.4 Hz, lH), 6.91 (d, J = 8.7 Hz, 2H), 7.39 (m, 5H), 7.39 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.9 Hz, lH); HRMS. Calcd for C ₃₁ H ₄₅ NO ₆ S: 560.3046. Found: 560.3043.

Example 1405

(4R-cis) -4- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido- 1-benzothiepin-5-yl] phenoxy-1-butanesulfonamide

Step 1: Preparation of Sulfonic Acid Intermediates

7.4 g (16.1 mmol) of 5 '-(4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (obtained in Example 1402, step 10) ) Was treated with potassium carbonate powder (3.3 g, 24.1 mmol, 1.5 equiv) and 1,4-butane sulfone (2.5 mL, 24.1 mmol, 1.5 equiv) and stirred under 25 ° C. and N ₂ atmosphere. Heated to 65 ° C. for 64 h. The solution was cooled to 25 ° C. and quenched by addition of water (50 mL) until a homogeneous mixture was obtained. The clear colorless solution was added dropwise to 4N HCl solution cooled to 0 ° C. for 30 minutes. The mixture was vigorously stirred for 4 hours, then warmed to room temperature and stirred for an additional 16 hours. The white precipitate obtained was filtered, washed with water and dried in vacuo to yield 8.8 g (92%) of the desired sulfonic acid as a white solid. A part of white solid was recrystallized from CH ₃ CN / hexanes to give the desired sulfonic acid as a colorless needle. mp 229-236 ° C. (decomposition); ¹ H NMR (DMSO-d ₆ ) δ 0.82 (m, 6H), 1.2 -1.33 (br m, 10H), 1.59 (m, lH), 1.73 (m, 4H), 2.00 (s, lH ), 2.48 (m, 2H), 2.71 (s, 6H), 2.98 (s, lH), 3.86 (s, lH), 3.93 (m, 2H), 5.08 (s, lH), 5.89 (s, lH) 6.52 (dd, J = 8.9, 2.4 Hz, lH), 6.92 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.l Hz, 2H), 7.60 (d, J = 8.9 Hz, 1H); Anal. Calc'd for C ₃₀ H ₄₅ NO ₇ S ₂ : C, 60.48; H, 7.61; N, 2.35. Found: C, 60.53; H, 7. 70; N, 2.42.

Step 2: Preparation of 7- (dimethylamino) -benzothiepin-5-yl] phenoxy-1-butanesulfonamide

To the solution of 1.12 g (1.88 mmol) of sulfonic acid obtained in step 1 in 10 mL of CH ₂ Cl ₂ was added 785 mg (3.77 mmol) of PCl ₅ and stirred for 1 hour. Water was added, ?? the rock was extracted and washed with brine. Drying with MgSO ₄ , filtration and solvent evaporation. To the residue was added 30 ml of 0.5 M NH _{3 in} dioxane and stirred for 16 h. The precipitate was filtered off and the solvent evaporated. The residue was purified by HPLC (using 33% EtOAc in hexanes) to afford the title compound as a beige solid (125 mg, 11%). mp 108-110 ° C.; ¹ H NMR (CDC1 ₃ ) δ 0.85-0.93 (m, 6H), 1.13-1.59 (m, 10H), 1.60-1.67 (m, lH), 1.94-2.20 (m, 5H), 2.82 (s, 6H) , 2.99 (d, J = 15: 3 Hz, lH), 3.15 (t, J = 15.3 Hz, lH), 3.23 (t, J = 7.7 HZ, 2H), 4.03 (t, J = 5.8 Hz, 2H) , 4.08-4.10 (m, lH), 4.79 (s, 2H), 5.47 (s, lH), 6.02 (d, J = 2.4 Hz, lH), 6.52 (dd, J = 8.9, 2.6 Hz, lH), 6.91 (d, J = 8.9 HZ, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.9 Hz, lH). HRMS. Calcd for C ₃₀ H ₄₇ N ₂ 0 ₆ S ₂ : 595.2876. Found: 595.2874.

Example 1406

(4R-cis) -1- [3- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxido-1-benzothiepin-5-yl] phenoxy] propyl] 4-aza-1-azoniabicyclo [2.2.2] octane, methanesulfonate (salt)

Step 1: Preparation of Dimesylate Intermediates

15.8 g (137.9 mmol) of methanesulfonyl chloride was added to a cooled (-20 占 폚) solution in which 5.0 g (65.7 mmol) of 1,3-propanediol was dissolved in 50 mL of triethylamine and 200 mL of methylene chloride. The mixture was stirred for 30 minutes, then warmed to room temperature and fractionated with ethyl acetate and 1N HCl. The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo to give 13.5 g (89%) of the dimesylate intermediate as a clear yellow oil. ¹ HNMR (CDCl ₃ ) δ 2.l2 (quadrant, J = 4.5 Hz, 4H), 3.58 (s, 6H), 4.38 (t, J = 5.4 Hz).

Step 2: Preparation of Propyl Mesylate Intermediates

Example 1402 2.4 g (5.2 mmol) of 5- (4′-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide obtained in step 10 and dimesylate intermediate (in step 1 Obtained) 3.6 g (26.1 mmol) of K ₂ CO ₃ was added to a solution of 6.0 g (26.1 mmol) dissolved in 50 ml of acetone. The reaction was heated to reflux overnight, cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo. Silica gel chromatography (Waters-Prep 500) purification using 36% ethyl acetate / hexanes gave 2.8 g (90%) of propyl mesylate intermediate as a white foam. ¹ H NMR (CDCl ₃ ) δ 0.86-0.95 (m, 6H), l.06-1.52 (m, 10H), 1.57-1.70 (m, lH), 2.14-2.32 (m, 3H), 2.84 (S, 6H), 3.02 (S, 3H), 3.08 (AB _q , J _AB = 15.0 Hz, J = 46.9 HZ, 4.09-4.18 (m, 3H) .4.48 (t, J = 6.0 HZ, 2H), 5.49 (S , lH), 6.l1 (s, lH), 6.65 (d, J = 8.7 Hz, lH), 6.94 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.9 Hz, lH).

Step 3: Preparation of Quaternary Salts

0.3 g (2.9 mmol) of 1,4-diazabicyclo [2.2.2] octane (DABCO) was added to a solution of 1.2 g (2.0 mmol) of the propyl mesylate intermediate obtained in Step 2 in 20 ml of acetonitrile. The reaction mixture was stirred at 60 ° C. for 3 hours, then cooled to room temperature and concentrated in vacuo. Polishing and purification with methylene chloride / ethyl ether gave 1.3 g (91%) of the title compound as the white solid. mp. (dec) 230-235 ° C .; ¹ H NMR (CDCl ₃ ) δ 0.86-0.95 (m, 6H), 1.04-1.52 (m, 10H), 1.57-1.70 (m, lH), 2.12-2.25 (m, 3H), 2.28-2.39 (m, 2H), 2.83 (S, 6H), 3.04 (S, 3H), 3.09 (AB _q , J _AB = 15.6 Hz, J = 42.2 HZ, 2H) 3.22-3.32 (m, 6H), 3.56-3.66 (m, 6H), 3.73-3.83 (m, 2H), 4.06-4.17 9m, 3H), 5.47 (s, 1H), 5.97 (s, lH), 6.51 (d, J = 8.6 Hz, lH), 6.90 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.9 Hz, lH). MS (ES +) m / e 612.4. HRMS (ES &lt; + &gt;) Calcd for C ₃₅ H ₅₄ N ₃ 0 ₄ S ⁺ : 612.3835. Found: 612.3840.

Example 1407

(4R-cis) -1- [3- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxido-1-benzothiepin-5-yl] phenoxy] propyl] -4-aza-1-azoniabicyclo [2.2.2] octane, 4-methylbenzenesulfonate (salt)

Step 1: Preparation of Propyl Tosylate Intermediates

Example 1402, 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (5.0 g, 10.9 mmol) obtained in step 10 was added to acetone (100 mL). The solution dissolved under N ₂ at 25 ° C. was treated with K ₂ CO ₃ (3.8 g, 27.2 mmol, 2.5 equiv) powder and 1,3-propanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 equiv) The resulting mixture was stirred at 65 ° C. for 21 hours. The cream slurry was cooled to 25 ° C. and filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous NaHCO ₃ solution (2 × 150 mL) and saturated aqueous NaCl solution (2 × 150 mL), dried (MgSO ₄ ) and concentrated in vacuo to give a pale orange oil. Flash chromatography (4.4x35 cm silica, 20-30% EtOAc / hexanes) purified to afford propyl tosylate intermediate (6.0 g, 80%) as a white foam. ¹ HNMR (CDCl ₃ ) δ 0.91 (m, 6H), 1.11-1.47 (br m, 10H), 1.63 (m, lH), 2.14 (m, 2H), 2.21 (m, lH), 2.41 (s, 3H ), 2.81 (s, 6H), 3.06 (ABq, J = 15.l Hz, J = 49.0 Hz, 2H), 4.01 (t, J = 5.3 Hz, 2H), 4.l0 (m, lH), 4.26 (t, J = 5.9 Hz, 2H), 5.29 (s, lH), 5.48 (s, lH), 5.98 (s, lH), 6.51 (dd, J = 8.9, 1.8 Hz, lH), 6.83 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.l Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.9 Hz, lH).

Step 2: Preparation of the Quaternary Salt

Diazabicyclo [2.2.2] octane (DABCO, 0.26 g, 2.34 mmol) in which the propyl tosylate intermediate (1.05 g, 1.56 mmol) obtained in step 1 was dissolved in acetonitrile (15 mL) at 25 ° C. and N _2. , 1.5 equivalents), and stirred at 50 ° C. for 6 hours and then at 25 ° C. for 14 hours. The amber solution was cooled to 25 ° C. and concentrated in vacuo to give an amber oil. The residue was dissolved in a minimum amount of CH ₂ Cl ₂ (5 mL) and diluted with Et ₂ O (100 mL) with vigorous stirring for 4 hours, during which time a white solid precipitated. This white solid was collected (Et ₂ O washed) to afford the title compound (1.11 g, 90%) as a white amorphous solid. mp 136.5-142 ° C. (decomposition); ¹ H NMR (CDCl ₃ ) δ 0.89 (m, 6H), 1.12-1.43 (br m, 9H), l.61 (m, lH), 1.65 (m, lH), 2.18 (m, lH), 2.22 ( m, 2H), 2.27 (s, 3H), 2.78 (s, 6H). 3.07 (ABq, J-15.l Hz, J = 39.5 Hz, 2H), 3.49 (br s, 6H), 3.68 (m, lH), 3.74 (br s, 6H), 3.96 (br s, 2H), 4.09 (d, J = 7.3 Hz, lH), 5.46 (s, lH), 5.96 (d, J = 2.4 Hz, lH), 6.49 (dd, J = 8.9, 2.4 Hz, lH), 6.83 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.l Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 8.l Hz, 2H), 7.87 (d , J = 8.9 Hz, lH); HRMS. Calcd for C ₃₅ H ₅₄ N ₃ O ₄ S: 6l2.3835. Found: 612.3832.

Example 1408

(4R-cis) -1- [4- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxydo-1-benzothiepin-5-yl] phenoxy] butyl] -4-aza-1-azoniabicyclo [2.2.2] octane methanesulfonate (salt)

Step 1: Preparation of Butyl Mesylate Intermediate

5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiefine-1,1-dioxide (obtained in Example 1402, step 10) 1.00 g (2.18 mmol), 2.68 g of busulfan 10.88 mmol) and 1.50 g (10.88 mmol) of potassium carbonate were added to 20 ml of acetone. The mixture was heated to reflux overnight. The mixture was concentrated in vacuo to dissolve the crude in 30 ml of ethyl acetate. The insoluble solid was filtered off and the filtrate was concentrated in vacuo. The resulting white foam was chromatographed through a silica gel column where 1.02 g (77%) of butyl mesylate intermediate was obtained as a white solid using 30% ethyl acetate / hexane as eluent. ¹ H NMR (CDC1 ₃ ) δ 0.90 (m, 6H), 1.20 −1. 67 (m, 12H), 1.98 (m, 4H), 2.22 (m, lH), 2.83 (s, 6H), 3.04 (s, 3H), 3.08 (ABq, 2H), 4.05 (t, J = 5.55 Hz , 2H), 4.11 (d, J = 6.90 Hz, lH), 4.35 (t, J = 6.0 Hz, 2H), 5.49 (s, lH), 6.00 (d, J = 2.4 Hz, lH), 6.52 (dd , J = 9.0 HZ, 2.7 Hz, lH), 6.93 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 8.4 HZ, 2H), 7.90 (d, J = 9.0 Hz, lH).

Step 2: Preparation of Ester Intermediates

The solution of 520 mg (0.85 mmol) of butyl mesylate intermediate obtained in step 1 and 191 mg (1.71 mmol) of DABCO in 10 ml of acetonitrile was stirred at 80 ° C. for 4 hours. The reaction mixture was concentrated in vacuo to give a white foam. This foam was triturated and washed with ether. The solid was filtered off and dried in vacuo to afford 540 mg (88%) of the title compound as desired, which was recrystallized from methylene chloride and acetone to give a white solid. mp 248-251 ° C; ¹ H NMR (CDCl ₃ ) δ 0.91 (m, 6H), l.14-1.47 (m, 14H), 1.63 (m, lH), 1.96 (m, 4H), 2.21 (m, lH), 2.77 (s , 3H), 2.82 (s, 3H), 3.07 (ABq, 2H), 3.26 (t, J = 7.l Hz, 6H), 3.60 (m, 8H), 4.08 (m, 3H), 5.47 (s, 1H), 5.99 (d, J = 2.4 Hz, lH), 6.51 (dd, J = 8.9 Hz, 2.6 Hz, lH), 6.91 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8. lHz, 2H), 7.89 (d, J = 9.0 Hz, lH).

Example 1409

(4R-cis) -1- [4- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxido-1-benzothiepin-5-yl] phenoxy] butyl] -4-aza-1-azoniabicyclo [2.2.2] octane-4-methylbenzenesulfonate (salt)

Step 1: Preparation of Propyl Tosylate Intermediates

Example 1402, 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (5.0 g, 10.9 mmol) obtained in step 10 was acetone at 25 ° C., N 2. The solution dissolved in (100 mL) was treated with K ₂ CO ₃ powder (3.8 g, 27.2 mmol, 2.5 equiv) and 1,4-butanediol di-p-tosylate (13.0 g, 32.6 mmol, 3.0 equiv), The resulting solution was cooled to 25 ° C. and filtered through a sintered glass funnel. The filtrate was concentrated and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with saturated aqueous NaHCO ₃ (2 × 150 mL) and saturated aqueous NaCl solution (2 × 150 mL). The extract was dried (MgSO ₄ ) and concentrated in vacuo to give a pale orange oil. Flash chromatography (4.4x35 cm silica, 20-30% EtOAc / hexanes) purified to afford propyl tosylate intermediate (6.0 g, 80%) as a white foam.

¹ H NMR (CDCl ₃ ) δ 0.89 (m, 6H), 1.10-│.44 (br m, 10H), 1.6│ (m, lH), 1.84 (m, 4H), 2.19 (m, lH), 2.43 (s, 3H), 2.80 (s, 6H), 3.03 (ABq, J-15.l Hz, J = 46.3 Hz, 2H), 3.93 (m, 2H), 4.06-4.13 (m, 4H), 5.44 ( s, lH) 5.96 (s, 1H), 6.46 (dd, J = 8.9, 1.4 Hz, lH), 6.85 (d, J = 8.l Hz, 2H), 7.33 (d, J = 8.l Hz, 2H), 7.38 (d, J = 8.l Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.83 (m, lH).

Step 2: Preparation of the Quaternary Salt

Diazabicyclo [2.2.2] octane (DABCO, 1.1 g, 10.1 mmol) in which the propyl tosylate intermediate (5.8 g, 8.5 mmol) obtained in step 1 was dissolved in acetonitrile (100 mL) at 25 ° C. and N ₂ . , 1.2 equiv) and stirred at 45 ° C. for 6 h. The pale yellow solution was cooled to 25 ° C. and concentrated in vacuo to yield an off white solid. The residue was dissolved in a minimum amount of CH ₂ Cl ₂ (5 mL) and diluted with Et ₂ O (100 mL) with vigorous stirring for 3 h during which time a white solid precipitated. This white solid was collected and recrystallized from EtOAc / hexanes to give the title compound (5.7 g, 85%) as a colorless needle.

mp 223 -231 ° C (decomposition); ¹ H NMR (CDCl ₃ ) δ 0.86 (m, 6H), 1.09-1.43 (br m, l 2 H), 1.61-1.90 (br m, 5H). 2.13 (m, lH), 2.25 (s, 3H), 2.75 (s, 6H), 3.03 (ABq, J = 15.1 Hz, J = 30.0 Hz, 2H), 3.05 (br s, 6H), 3.37 (br s , 6H), 3.89 (m, 2H), 4.07 (d, J = 7.5 Hz, lH), 5.39 (s, 2H), 5.97 (d, J = 1.6 Hz, lH), 6.44 (dd, J = 8.9, 2.0 Hz, lH), 6.87 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.l Hz, 2H), 7.37 (d, J = 8.3 HZ, 2H), 7.71 (d, J = 8.l Hz, 2H), 7.80 (d, J = 8.9 H2, 1H); HRMS. Calcd for C ₃₆ H ₅₆ N ₃ 0 ₄ S: 626.3992. Found: 626.3994.

Elemental Analysis for C ₄₃ H ₆₃ N ₃ O ₇ S ₂ :

Calculated: C, 64.71; H, 7.96; N, 5.27.

Found: C, 64.36; H, 8. 10; N, 5.32.

Example 1410

(4R-cis) -4- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido- 1-benzothiepin-5-yl] phenoxy] -N, N, N-triethyl-1-butaneaminium

A solution of 1 g (1.64 mmol) of butyl mesylate intermediate obtained in Example 1408, Step 1 and 15 ml of triethylamine in 10 ml of acetonitrile was heated at 50 ° C. for 2 days. The solvent was evaporated and the residue was triturated with ether and ethyl acetate to give 500 mg (43%) of product as semisolid. ¹ H NMR (CDCl ₃ ) δ 0.8 (m, 6 H), 1-1.6 (m, 24 H), 2.1 (m, lH), 2.6 (s, 3 H), 2.7 (s, 6 H), 2.9 (d, J = 15 Hz, lH), 3.0 (d, J = 15 Hz, lH), 3.3 (m, 8 H), 4.0 (m, 4 H), 5.3 (s, l H), 5.9 (s , l H), 6.4 (m, lH), 6.8 (d, J = 9 Hz, 2 H), 7.4 (d, J = 9 Hz, 2H). 7.8 (d, J = 7 Hz, lH). MS m / e 615.

Example 1411

(4R-cis) -1- [4- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxido-1-benzothiefin-5-yl] phenoxy] butyl] -3-hydroxypyridinium, methanesulfonate (salt)

Example 1408, a solution of 1 g (1.64 mmol) of butyl mesylate intermediate obtained in Step 1 and 234 mg (2.46 mmol) of 3-hydroxypyridine in 1 ml of dimethylformamide was heated at 70 ° C. for 20 hours. The solvent was evaporated and the residue was triturated with ether and ethyl acetate to give 990 mg (86%) of the product as a semisolid. ¹ H NMR (CDCl ₃ ) δ 0.9 (m, 6 H), 1-1.5 (m, 10 H), 1.7 (m, l H), 1.9 (m, 2H), 2-2.4 (m, 3 H) , 2.9 (s, 6 H), 3.1 (d, J = 15 Hz, lH), 3.2 (d, J = 15 Hz, lH), 4.1 (m, 3 H), 4.7 (m, 2

H), 5.5 (s, lH), 6.1 (s, lH), 6.6 (m, l H), 6.9 (d, J = 9 Hz, 2 H), 7.4 (d, J = 9 Hz, 2 H) , 7.7 (m, l H), 8.0 (m, 2 H), 8.2 (m, l H), 9.1 (s, l H). MS m / e 609.

Example 1412

(4R-cis) -1- [5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxido-1-benzothiefin-5-yl] phenoxy] pentyl] quinolinium, methanesulfonate (salt)

Step 1: Preparation of Pentyl Mesylate Intermediates

5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide in a solution in which 231 mg (5.79 mmol, 60% dispersion) of NaH was stirred and dissolved in 22 ml of DMF. Example 1402, obtained in step 10) 2.05 g (4.45 mmol) was added and the resulting solution was stirred at room temperature for 1 hour. 18.02 g (55.63 mmol) of 1,5-diiodopentane was added to the mixture, and the solution was stirred at room temperature overnight. DMF was removed under high vacuum and the residue was extracted with ethyl acetate and then washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give pentyl mesylate intermediate. ¹ H NMR (CDC1 ₃ ) δ 0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, lH), 2.8 (s, 6h), 3.0 (q, 2H), 3.22 (t, 2H ), 3.95 (t, 2H), 4.l (s, 1H), 5.42 (s, lH), 6.1 (d, lH), 6.6 (d, lH), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, lH).

Step 2: Preparation of the Quaternary Salt

To 1.0 g (1.53 mmol) of the pentyl mesylate intermediate obtained in step 1, 3.94 g (30.5 mmol) of quinoline and 30 ml of acetonitrile were added. This solution was heated to 45 ° C. under N ₂ for 10 days. The concentrated residue was purified by reverse phase C18 column chromatography. The material obtained was replaced with mesylate anion using ion exchange chromatography to afford the desired title compound as a solid. mp 136 ° C; ¹ H NMR (CDC1 ₃ ) δ 0.95 (q, 6H), 1.05-2.25 (m, 18H), 2.8 (s, 9H), 3.0 (q, 2H), 3.95 (t, 2H), 4.1 (s, lH ), 5.28 (t, 2H), 5.42 (s, lH), 5.95 (s, lH), 6.45 (d, lH), 6.82 (d, 2H), 7.4 (d, 2H), 7.82 (d, lH) , 7.9 (t, lH), 8.2 (t, 2H), 8.3 (q, 2H), 8.98 (d, lH), 10. 2 (d, lH). HRMS. Calcd for C ₄₀ H ₅₃ N ₂ O ₄ S: 657.3726. Found: 657.3736.

Elemental Analysis for C ₄₀ H ₅₃ N ₂ O ₄ S.CH ₃ O ₃ S:

Calculated: C, 65.40; H, 7. 50; N, 3.72; S, 8.52.

Found: C, 62.9; H, 7.42; N, 3.56; S, 8.41.

Example 1413

(4R-cis)-[5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido -1-benzothiepin-5-yl] phenoxy] pentyl] propanediic acid

Step 1: Preparation of the pentyl bromide intermediate

5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide in a solution of 0.63 g (15.72 mmol, 60% dispersion) of NaH was stirred and dissolved in 85 ml of DMF. Example 1402, obtained in step 10) 6.0 g (13.1 mmol) was added and the resulting solution was stirred at room temperature for 1 hour. 37.7 g (163.75 mmol) of 1,5-dibromopentane was added to the solution, and the mixture was stirred at room temperature overnight. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give pentyl bromide intermediate. ¹ H NMR (CDC1 ₃ ) δ 0.90 (q, 6H), 1.05-2.0 (m, 17H), 2.2 (t, lH), 2.8 (S, 6H), 3.0 (q, 2H), 3.4 (t, 2H ), 3.95 (t, 2H), 4.1 (s, lH), 5.42 (s, lH), 6.0 (s, lH), 6.5 (d, lH), 6.9 (d, 2H), 7.4 (d, 2H) , 7.9 (d, lH).

Step 2: Preparation of Dibenzyl Ester Intermediates

To a mixture of 59 mg (1.476 mmol, 60% dispersion) of NaH was added to 27 ml of THF and 9 ml of DMF at 0 ° C., 0.84 g (2.952 mmol) of dibenzyl malonate (Aldrich) was added. Stir for minutes. 0.5987 g (0.984 mmol) of the pentyl bromide intermediate was added to the solution, and the mixture was stirred at 80 ° C. overnight. The solvent was removed in vacuo and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give dibenzyl ester intermediate. ¹ H NMR (CDC1 ₃ ) δ 0.90 (q, 6H), 1.05-2.0 (m, l9H), 2.2 (t, lH), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t, lH ), 3.9 (t, 2H), 4.1 (d, lH), 5.18 (s, 4H), 5.42 (s, lH), 5.95 (s, 1H), 6.5 (d, lH), 6.9 (d, 2H) 7.2-7.4 (m, 12H), 7.85 (d, lH).

Step 3: Preparation of Diacid

A suspension of 0.539 g (0.664 mmol) of dibenzyl ester intermediate obtained in Step 2 and 25 mg of 10% Pd / C in 30 ml of ethanol was stirred under 20 psi of hydrogen gas at room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated to give the desired title compound as a solid. mp ll8 ° C; ¹ H NMR (CDCl ₃ ) δ 0.9 (d, 6H), 1.05-2.2 (m, 20H), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (s, lH), 3.95 (s, 2H ), 4.1 (s, lH), 5.42 (s, lH), 5.95 (s, lH), 6.5 (d, lH), 6.9 (d, 2H), 7.4 (d, 2H), 7.85 (d, lH) . HRMS. Calcd for C ₃₄ H ₄₉ NO ₈ S: 632.3257. Found: 632.3264.

Elemental Analysis for C ₃₄ H ₄₉ NO ₈ S

Calculated Value: C, 64.63; H, 7. 82; N, 2.22; S, 5.08.

Found: C, 63.82; H, 7.89; N, 2.14; S, 4.93.

Example 1414

(4R-cis) -3,3-dibutyl-5- [4-[[5- (diethylamino) pentyl] oxy] phenyl] -7- (dimethylamino) -2,3,4,5-tetra Hydro-1-benzothien-4-ol 1,1-dioxide

Step 1: Preparation of Pentyl Iodide Intermediates

Example 1402, 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (3 g, 6.53 mmol) obtained in step 10 was dissolved in 100 ml of dimethylformamide. 198 mg (7.83 mmol) of 95% sodium hydride was added to the solution. The mixture was stirred at room temperature for 15 minutes and diiodopentane was added. After 1 h at rt, the mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography eluting with hexane / ethyl acetate (1/5) to afford 2.92 g (4.46 mmol) of pentyl iodide intermediate. ¹ H NMR (CDCl ₃ ) δ 0.9 (m, 6 H), 1-1.5 (m, 1l H), 1.6 (m, 3 H), 1.8 (m, 4 H), 2.2 (m, lH), 2.8 (s, 6H), 3.0 (d, J = 15 Hz, 1H), 3.2 (d, J = 15 HZ, lH), 3.3 (m, 2H), 4.0 (m, 1H), 4.1 (s, l H), 5.5 (s, l H), 6.1 (s, l H), 6.6 (m, lH), 6.9 (d, J = 9 Hz, 2 H), 7.4 (d, J = 9 Hz, 2 H), 7.9 (d, J = 7 Hz, lH).

Step 2: Preparation of the Amine

A solution of 550 mg (0.76 mmol) of pentyl iodide intermediate (obtained in step 1) and 279 mg (3.81 mmol) of diethylamine in 3 ml of acetonitrile was stirred at 100 ° C. overnight. The mixture was concentrated in vacuo to give a tan foam. This foam was dissolved in 10 ml of ethyl acetate and washed twice with 50 ml of saturated sodium carbonate solution. This ethyl acetate layer was dried over magnesium sulfate and concentrated to afford 390 mg (85%) of the title compound as a yellow effervescent solid. ¹ H NMR (CDCl ₃ ) δ 0.89 (m, 6H), 1.20-1.47 (m, 12H), 1.53-l.67 (m, 4H), 1.76-1.90 (m, 8H), 2.21 (m, lH) , 2.74-2.92 (m, 12H), 3.07 (ABq, 2H), 4.00 (t, J = 6.3 Hz, 2H), 4.l0 (d, J = 7.8 Hz, lH), 5.48 (s, lH), 6.00 (d, J = 2.4 Hz, lH), 6.51 (dd, J = 9.2 Hz, 2.6 Hz, lH), 6.92 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.4 HZ, 2H) , 7.90 (d, J = 9.0 Hz, lH).

Example 1415

(4R-cis) -N- (carboxymethyl) -N- [5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydrate Oxy-1,1-dioxido-1-benzothiepin-5-yl] phenoxy] pentyl] glycine

Step 1: Preparation of Diester Intermediates

A mixture of 8.6 g (14.1 mmol) of pentyl bromide intermediate obtained in Example 1413, step 1, 65 g (0.35 mol) of diethylaminodiacetate and 7.5 g (71 mmol) of anhydrous Na ₂ CO ₃ was stirred at 160 ° C. for 3 hours. . The reaction mixture was diluted with water and extracted with methylene chloride. The volatiles were removed in vacuo to yield 9.6 g (95%) of diester intermediate. ¹ H NMR spectrum was consistent with the above structure; MS (M + H) m / e 717.

Step 2: Preparation of Diacid

The mixture obtained by adding the diester intermediate obtained in Step 1 and 2.7 g (64.3 mmol) of LiOH to THF (75 mL) and water (50 mL) was stirred at 40 ° C. for 18 hours. The reaction mixture was acidified with 1% HCl and extracted with dichloromethane. The residue was triturated with hexanes and filtered to give 8.9 g (93%) of the title compound as the solid. mp 148-162 ° C. ¹ H NMR (CD ₃ OD) δ 0.92 (t, 6H), 1.1-1.9 (m, 31H), 2.l5 (t, 1H), 2.8 (s, 6H), 3.15 (ABq, 2H) 3.75 (m , lH), 4.1 (m, 6H), 5.3 (s, lH), 6.1 (s, 1H), 6.6 (d, lH), 7.0 (d, 2H), 7.4 (d, 2H), 7.8 (d, lH); MS (M + H) m / e 661.

Elemental Analysis for [C ₃₅ H ₅₂ N ₂ O ₈ S + 1.5H ₂ O]:

Calculated: C, 61.11; H, 8.06; N, 4.07; S, 4.66.

Found: C, 61.00; H, 7.72; N, 3.89; S, 4.47.

Example 1416

(4R-cis)-[5- [4-[[5- [bis [2- (diethylamino) ethyl] amino] pentyl] oxy] phenyl] -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-1-benzothien-4-ol 1,1-dioxide

A solution of 1 g (1.53 mmol) of the pentyl iodide intermediate obtained in Example 1414, Step 1 in N, N, N ', N'-tetraethyl diethylenetriamine was heated to 80 ° C. for 4 hours. This mixture was dissolved in ethyl acetate and saturated NaHCO ₃ . The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography. Fractions containing product were concentrated in vacuo, dissolved in ethyl acetate and washed with saturated NaHCO ₃ . The residue was dried and concentrated in vacuo to afford 840 mg (74%) of the title compound as a thick oil. ¹ H NMR (CDC1 ₃ ) δ 0.8 (m, 6 H), 1-1.6 (m, 28 H), 1.8 (m, 2 H), 2.1 (m, l H), 2.5 (m, 18 H), 2.7 (s, 6H) 2.9 (d, J = 15 Hz, lH), 3.1 (d, J = 15 Hz, lH), 3.9 (m, 2H), 4.0 (m, lH), 4.l ( s, lH), 5.4 (s, lH), 6.0 (s, lH), 6.4 (m, lH), 6.9 (d, J = 9 Hz, 2H), 7.4 (d, J = 9 Hz, 2H ), 7.8 (d, J = 7 Hz, lH). MS (M + H) m / e 743.

Example 1417

(4R-cis) -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-5- [4-[[5 [[[2- (1H-imidazole-) 4-yl) ethyl] amino] pentyl] oxy] phenyl] -1-benzothien-4-ol 1,1-dioxide

A solution of 1 g (1.53 mmol) of pentyl iodide intermediate obtained in Example 1414, Step 1 and 3.4 g (30.6 mmol) of histamine was heated to 50 ° C. for 17 hours. This mixture was dissolved in ethyl acetate and saturated NaHCO ₃ . The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ether to give 588 mg (60%) of the title compound as a semisolid. ¹ H NMR (CDCl ₃ ) δ 0.9 (m, 6 H), ll.7 (m, l4H), 1.9 (m, 3 H), 2.0 (m, 2 H), 2.2 (m, l H), 2.8 (s, 6H), 3.0 (m, 3H), 3.2 (m, 2H), 4.0 (m, 2H), 4.1 (m, 3H), 5.5 (s, lH), 6.0 (s, 1H), 6.5 (m, lH), 6.8 (s, lH), 6.9 (d, J = 9 Hz, 2 H), 7.4 (m, 3 H), 7.9 (d, J = 8 Hz, l H) . MS (M + H) m / e 639.

Example 1418

(4R-cis) -N- [5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxido-1-benzothiepin-5-yl] phenoxy] pentyl] -N'-ethyl-N, N, N ', N'-tetramethyl-1,2-ethanediammonium dichloride

Step 1: Preparation of the pentyl bromide intermediate

Example 1402, 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (1.680 g, 3.66 mmol) obtained in step 10 and sodium hydride (0.250 g, 6.25 mmol) was added to 30 mL of DMF, and the mixture was stirred in anhydrous 100 mL round bottom flask under N ₂ . 1,5-Dibromopentane (6.0 mL / 44.0 mmol) was added to this solution, and the resulting mixture was stirred for 18 hours. The reaction was diluted with brine (100 mL) and water (20 mL) and the mixture was extracted with EtOAc (3x50 mL). The organic layers were combined, dried (MgSO ₄ ), filtered and concentrated in vacuo. Filtration was carried out through silica gel, eluting with 20% EtOAc / hexanes, and evaporated in vacuo to give the pentyl bromide intermediate as a white effervescent solid (1.783 g, 80%). ¹ H NMR (CDCl ₃ ) δ 0.84-0.95 (m, 6H), 1.02-l.56 (m, 10H), 1.58-1.70 (m, 3H), 1.78-2.03 (m, 4H), 2.15-2.24 ( m, lH), 2.77 (s, 1H), 2.80 (s, 6H), 3.05 (ABq, 2H), 3.42 (t, 2H), 3.98 (t, 2H), 4.10 (s, lH), 5.47 (s , lH), 5.99 (d, lH), 6.50 (dd, lH), 6.91 (d, 2H), 7.40 (d, 2H), 7.88 (d, lH).

Step 2: Preparation of Mono Quaternary Salt

The mixture of pentyl bromide intermediate (0.853 g, 1.40 mmol) and N, N, N ', N'-tetramethylethylenediamine (1.0 mL / 6.62 mmol) obtained in step 1 was added to 30 mL of acetonitrile. Stirred for hours and the reaction mixture was concentrated in vacuo to give an off white foamy solid (1.052 g). The crude product was dissolved in acetonitrile (1.5 mL) and ground with ethyl ether. The solvent was decanted to give a sticky solid. Polishing was repeated twice, and the resulting viscous solid was concentrated in vacuo to give a mono quaternary salt as an off-white foamy solid (0.951 g, 94%). ¹ H NMR (CDCl ₃ ) δ 0.81 (t, 6H), 0.96-1.64 (m, 13H), 1.62-1.85 (m, 4H), 2.03-2.18 (m, lH), 2.20 (s, 6H), 2.67 (t, 2H), 2.74 (s, 6H), 2.98 (ABq, 2H), 3.30-3.42 (m, lH), 3.38 (s, 6H), 3.60-3.75 (m, 4H), 3.90 (t, 2H ), 4.01 (s, lH), 5.37 (s, lH), 5.92 (s, lH), 6.41 (dd, lH), 6.81 (d, 2H), 7.32 (d, 2H), 7.77 (d, lH) .

Step 3: Preparation of Diquatitis

The monoquat salt (0.933 g, 1.29 mmol), iodoethane (0.300 mL / 3.75 mmol) and acetonitrile (30.0 mL) obtained in step 2 were mixed in a 4 oz Fisher Porter bottle. The reaction vessel was purged with N ₂ , sealed, and then heated to 50 ° C. with a magnetic stirrer. After 24 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo to yield a yellow foamy solid (1.166 g). This solid was dissolved in methylene chloride / acetonitrile and precipitated with ethyl ether. After cooling to 0 ° C. overnight, the resulting solid was filtered, washed with ethyl ether and concentrated in vacuo to give the diquatary salt as an off-white solid (1.046 g, 92%). ¹ H NMR (CD ₃ OD) δ 0.59 (t, 6H), 0.70-1.10 (m, 9H), 1.16 (t, 3H), 1.22-1.80 (m, 9H), 2.42 (s, 6H), 2.78 ( d, 2H), 2.98 (s, 6H), 3.02 (s, 6H), 3.22-3.37 (m, 4H), 3.63-3.78 (m, 4H), 3.80 (s, 4H), 4.93 (s, lH) , 5.71 (s, lH), 6.22 (dd, lH), 6.61 (d, 2H), 7.02 (d, 2H), 7.40 (d, 1H).

Step 4: Preparation of Quaternary Dichloride Salts

The iodobromo salt obtained in step 3 was converted to the corresponding dichloride salt, eluting with 70% H ₂ O / acetonitrile using Biorad AG 2X8 resin to convert the desired title compound into a white effervescent solid (0.746 g). , 84%). mp 193.0-197.0 ° C .; ¹ H NMR (CD ₃ OD) δ 0.59 (t, J = 6.0 HZ, 6H), O.70-1.12 (m, 9H), 1.16 (t, J = 6.6 Hz, 3H), 1.24-1.90 (m, 9H), 2.50 (S, 6H), 2.78 (s, 2H), 3.08 (s, 6H), 3.1l (S, 6H), 3.24-3.50 (m, 4H), 3.68 (s, 2H), 3.81 ( s, 2H), 4.16 (s, 4H), 5.02 (s, lH), 5.72 (S, lH), 6.l9 (d, J = 8.4 Hz, lH), 6.61 (d, J = 8.l Hz , 2H), 7.10 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.7 Hz, lH). HRMS. Calcd for C ₃₉ H ₆₇ N ₃ O ₄ SCl: 708.4541. Found: 708.4598.

Example 1419

[4R- [4a, 5a (4R *, 5R *)]]-N, N'-bis [5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4, 5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl] phenoxy] pentyl] -N, N, N ', N'-tetramethyl-1,6 Hexanediammonium dichloride

5 ml of acetonitrile with pentyl bromide intermediate (1.002 g, 1.64 mmol) and N, N, N ', N'-tetramethyl-1,6-hexanediamine (0.100 g, 0.580 mmol) obtained in step 1 of Example 1418. The solution dissolved in was poured into a 4 oz Fisher Potter bottle. The reaction vessel was purged with N ₂ , sealed, and then heated to 50 ° C. with a magnetic stirrer. After 15 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo to yield an off white foamy solid (1.141 g). The solid was dissolved in acetonitrile and precipitated with ethyl ether. After cooling to 0 ° C., the solvent was decanted to give a sticky off-white solid. This polishing step was repeated, and the resulting viscous solid was concentrated in vacuo to afford the desired dibromide salt as an off-white foamy solid (0.843 g, quantitative). ¹ H NMR (CDC1 ₃ ) δ O.85 (m, 12H), 1.01-1.70 (m, 30H), 1.76-2.08 (m, 12H), 2.18 (t, J = 12.3 Hz, 2H), 2.79 (s , l2H), 3.03 (ABq, 4H), 3.35 (s, 12H), 3.52 (br s, 6H), 3.72 (br s, 4H), 3.97 (br s, 4H), 4.08 (br s, 2H), 5.42 (s, 2H), 6.00 (S, 2H), 6.51 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 7.8 Hz, 4H), 7.38 (dJ = 7.8 Hz, 4H), 7.83 ( d, J = 8.7 Hz, 2H). This dibromide salt was converted to the corresponding dichloride salt, eluting with 70% H ₂ O / CH ₃ CN using Biorad AG 2X8 resin to yield the desired title compound as a white effervescent solid (0.676 g, 86%). Obtained as mp 178.0-182.0 ° C .; ¹ H NMR (CDC1 ₃ ) δ 0.80-0.90 (m, 12H), 1.01-1.70 (m, 30H), 1.75-2.06 (m, 12H), 2.16 (t, J = 12.9 Hz, 2H), 2.79 (s , 12H), 3.03 (ABq, 4H), 3.33 (s, 12H), 3.49 (brs, 6H), 3.70 (br s, 4H), 3.96 (t, J = 5.4 Hz, 4H), 4.08 (s, 2H ), 5.42 (s, 2H), 5.986 (s, lH), 5.993 (s, lH), 6.49 (d, J = 9.0 Hz, lH), 6.50 (d, J = 9.O Hz, lH), 6.87 (d, J = 8.4 Hz, 4H), 7.38 (d, J = 8.l Hz, 4H), 7.84 (d, J = 8.7 Hz, 2H). HRMS. Calcd for C ₃₆ H ₅₈ N ₂ 0 ₄ S: 614.4118. Found: 614.4148.

Example 1420

(4R-cis) -3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-5- [4-[[5- (1H-tetrazol-5-yl) Pentyl] oxy] phenyl] -1-benzothien-4-ol 1,1-dioxide

Step 1: Preparation of the pentyl bromide intermediate

5- (4'-hydroxyphenyl) -7- (dimethylamino) obtained in Example 1402, step 10 in a suspension suspended by adding 1.01 g (25.4 mmol, 60% oil dispersion) of sodium hydride to 150 ml of DMF. 9.0 g (19.5 mmol) of tetrahydrobenzothiene-1,1-dioxide were added in portions. After 30 minutes, the reaction was cooled in a water bath (15 ° C.) and 4.48 g (195 mmol) of 1,5-dibromopropane were added. The reaction was stirred at room temperature for 1.5 hours and quenched with 50 ml of saturated NH ₄ Cl solution. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Silicagel chromatography (Waters-Prep 500) purification using 25% ethyl acetate / hexanes afforded 10.17 g (85%) of pentyl bromide intermediate as a colorless foam. mp 65 -70 ° C; ¹ H NMR (CDCl ₃ ) δ 0.84-0.98 (M, 6H), 1.04-1.52 (m, 10H), 1.58-1.65 (m, 3H), 1.82 (p, J = 6.8 Hz, 2H), 1.94 (p, J = 7.0 Hz, 2H), 2.12-2.26 (m, lH) 2.82 (S, 6H), 3.06 (AB _q , J _AB = 15.2, 45.3 HZ, 2H), 3.44 (t, J = 6.7 Hz , 2H), 3.99 (t, J = 6.3 Hz, 2H), 4.10 (s, lH), 5.47 (s, lH), 6.15 (d, J = 2.7 Hz, lH), 6.68 (dd, J = 2.5, 8.4 Hz, lH), 6.91 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.7 Hz, lH).

Step 2: Preparation of the pentyl nitrile intermediate

To a solution of 378 mg (0.621 mmol) of the pentyl bromide intermediate obtained in Step 1 in 1 mL of DMSO was added 37 mg (0.745 mmol) of sodium cyanide. The reaction was stirred at room temperature for 16 hours. The reaction was concentrated under nitrogen and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give 278 mg (93% RP-HPLC purity, about 75%) of pentyl nitrile intermediate as a colorless foam. ¹ H NMR (CDCl ₃ ) δ 0.86-0.96 (m, 6H), 1.02-1.21 (m, lH), 1.21-1.52 (m, 19H), 1.58-1.92 (m, 7H), 2.16-2.28 (m, lH), 2.41 (t, J = 6.9 HZ, 2H), 2.83 (S, 6H), 3.08 (AB _q , 15.0, 47.5 HZ, 2H), 4.01 (t, J = 6.2 HZ, 2H), 4.1 (s , lH), 5.49 (s, lH), 6.07 (d, J = 2.l Hz, lH), 6.59 (dd, J = 2.4, 8.7HZ, lH), 6.92 (d, J = 8.l HZ, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.92 (d, J-8.7 HZ, lH). MS (ES, M + H) m / e 555.

Step 3: Preparation of Tetrazole

A solution of 275 mg (0.5 mmol) of nitrile intermediate obtained in Step 2 and 666 mg (3.23 mmol) of azidotrimethyltin in 5 ml of toluene was stirred for 60 hours while heating to 80 ° C. The reaction was concentrated under nitrogen. Purification by reverse phase chromatography (Waters-Delta Prep) using 60% water / acetonitrile gave 226 mg (75%) of the title compound as colorless foam. mp 80-85 ° C; ¹ H NMR (CDCl ₃ ) δ 0.83-0.95 (m, 6H), 1.30-1.52 (m, 10H), 1.52-1.73 (m, 3H), 1.79-1.99 (m, 4H), 2.14-2.26 (m, lH), 2.91 (s, 6H), 3.02-3.22 (m, 4H), 3.92-4.06 (m, 2H), 4.16 (s, lH), 5.47 (s, lH), 6.28 (d, J = 2.4 Hz , lH), 6.74 (dd, J = 2.7, 8.8 Hz, lH), 6.89 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.l Hz, 2H), 7.98 (d, J = 8.7 Hz, lH). HRMS calcd for C ₃₂ H ₄₈ N ₅ O ₄ S: 598.3427. Found: 598.3443.

Example 1421

(4R-cis) -4-[[5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1- Dioxydo-1-benzothiepin-5-yl] phenoxy] pentyl] oxy] -2,6-pyridinecarboxylic acid

Step 1: Preparation of Pentyl Bromide Intermediates

5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothier obtained in Example 1402, step 10 in a solution of 0.63 g (15.72 mmol, 60% dispersion) of sodium hydride in 85 mL of DMF. 6.0 g (13.1 mmol) of pin-1,1-dioxide was added and the resulting solution was stirred at room temperature for 1 hour. 27.7 g (163.75 mmol) of 1,5-dibromopropane were added to the solution, and the mixture was stirred overnight at room temperature. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give pentyl bromide intermediate. ¹ H NMR (CDCl ₃ ) δ 0.90 (q, 6H), l.05-2.0 (m, 17H), 2.2 (t, lH), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (t , 2H), 3.95 (t, 2H), 4.1 (s, lH), 5.42 (s, lH), 6.0 (s, lH), 6.5 (d, lH), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, lH).

Step 2: esterification of keladamic acid

10 g (54.6 mmol) of keladamic acid, 23.0 g (120.12 mmol) of 1- (3-dimethyl aminopropyl) -3 ethyl carbodiimide hydrochloride, 1.33 g (10.8 mmol) of 4-dimethylaminopyridine and 12.4 mL (120.12 mmol) of benzyl alcohol ) In 100 ml of DMF was stirred overnight at room temperature under N ₂ . The DMF was removed in vacuo and the residue was extracted with methylene chloride and washed with 5% NaHCO _3a , 5% acetic acid, H ₂ O and brine. This extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give dibenzyl keladamic acid ester. ¹ H NMR (CDCl ₃ ) δ 5.4 (s, 4H), 7.4 (m, 12H).

Step 3: Preparation of the pyridinyl benzyl ester intermediate

A solution of 79 mg of NaH (1.972 mmol, 60% dispersion) and 0.716 g (1.972 mmol) of dibenzyl kelidamic acid ester (obtained in step 2) in 17.5 ml of DMF was stirred at room temperature for 1 hour. To this solution was added 1.0 g (1.643 mmol) of pentyl bromide intermediate and the mixture was stirred overnight at 40 ° C. under N ₂ . DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. This extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give pyridinyl dibenzyl ester intermediate. ¹ H NMR (CDCl ₃ ) δ 0.90 (q, 6H), 1. 05 -2. 0 (m, 19H), 2.2 (t, lH), 2.8 (s, 6H), 3.0 (q, 2H), 4.0 (t, 2H), 4.l (s, 1H), 5.4 (s, 4H) , 5.42 (s, lH), 6.0 (s, lH), 6.5 (d, lH), 6.9 (d, 2H), 7.3-7.5 (m, 12H), 7.78 (s, 2H), 7.9 (d, lH ).

Step 4: Preparation of Pyridinyl Diacid

A suspension of 0.8813 g (0.99 mol) of dibenzyl ester (obtained in step 3) and 10 mg Pd / C 40 mg in 35 ml of ethanol and 5 ml of THF was stirred at room temperature under 20 psi of hydrogen gas for 2 hours. The catalyst was filtered off and the filtrate was concentrated to give the desired title compound as a solid. mp 143 ° C; ¹ H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 15H), 1.9 (m, 4H), 2.22 (t, lH), 2.8 (s, 6H), 3.0 (t, 2H ), 4.1 (s, 3H), 4.3 (s, 2H), 5.4 (s, 1H), 6.05 (s, lH), 6.5 (d, lH), 6.9 (d, 2H), 7.4 (d, 2H) , 7.78 (d, lH), 7.82 (s, 2H). HRMS. Calcd for C ₃₈ H ₅₀ N ₂ 0 ₉ S: 711.3315. Found: 711.3322.

Elemental Analysis for C ₃₈ H ₅₀ N ₂ O ₉ S

Calculated: C, 64.20; H, 7.09; N, 3.94; S, 4.51.

Found: C, 62.34; H, 6.97; N, 4.01; S, 4.48.

Example 1422

(4R-cis)-[5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido -1-benzothiepin-5-yl] phenoxy] pentyl] guanidine

Step 1: Preparation of the pentyl azide intermediate

To a solution of 200 mg (0.328 mmol) of the pentyl bromide intermediate obtained in Example 1420 and Step 1 in 0.75 mL of DMSO was added 32 mg (0.493 mmol) of sodium azide and a catalytic amount of sodium iodide. The reaction was stirred at room temperature for 64 hours. The reaction was concentrated under nitrogen and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give 155 mg (92% RPHPLC purity, about 76% yield) of pentyl azide intermediate as a colorless foam. This sample was used without further purification. mp 45-50 ° C .; ¹ H NMR (CDCl ₃ ) δ 0.83-0.93 (m, 6H), 1.03-1.48 (m, l0H), 1.54-1.74 (m, 5H), 1.78-l.86 (m, lH), 2.14-2.26 ( m, lH), 2.81 (S, 6H), 3.06 (AB _q , J _AB = 15.0, 48.0 HZ, 2H), 3.31 (t, J = 6.3 Hz, 2H), 3.98 (t, J = 6.3 Hz, 2H ), 4.09 (s, lH), 5.47 (s, lH), 6.10 (d, J = 1.8 Hz, lH), 6.63 (dd, J = 2.7, 9.0 Hz, lH), 6.91 (d, J = 9.0 Hz , 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.7 Hz, lH). MS (FAB, M + H) m / e 571.

Step 2: Preparation of Pentylamine Intermediates

0.10 g of 10% Pd / C was added to a solution of 0.67 g (1.17 mmol) of the azide intermediate obtained in step 1 in 75 mL of ethanol, and the mixture was shaken for 3.5 hours under 49 psi of hydrogen at room temperature. The reaction was filtered through celite and concentrated in vacuo to yield 0.62 g of pentyl amine intermediate as off-white foam. Samples were used without further purification. mp 70-85 ° C .; ¹ H NMR (CDCl ₃ ) δ 0.86-0.96 (m, 6H), 1.06-1.75 (m, 15H), 1.79-1.93 (m, 4H), 2.15-2.28 (m, lH), 2.82 (S, 6H) , 2.96-3.20 (m, 4H), 3.99 (t, J = 6.0 Hz, 2H), 4.O4-4.14 (m, 1H), 5.49 (s, lH), 6.00 (d, J = 1.5 Hz, lH ), 6.51 (d, J = 9.0 Hz, lH), 6.91 (d, J = 8.4 Hz, 2H), 7.4l (d, J = 8.l Hz, 2H), 7.90 (d, J = 8.7 Hz, lH). MS (ES, M + H) m / e 545.

Step 3: Preparation of Guanidine

71 mg of diisopropylethylamine in a solution in which 258 mg (0.474 mmol) of pentyl amino intermediate obtained in Step 2 and 81 mg (0.551 mmol) of 1H-pyrazole-1-carboxamidine hydrochloride were stirred and dissolved in 1.5 ml of DMF. 0.551 mmol) was added. The reaction was stirred at room temperature for 16 hours. Reversed-phase chromatography using 60% water / acetonitrile (Waters-Delta prep) purification gave 120 mg (43%) of the title compound as a colorless effervescent solid. mp 67.0-72.5 ° C; ¹ H NMR (CDCl ₃ ) δ 0.89-0.93 (m, 6H), 1.05-1.l7 (m, lH), 1.26-1.90 (m, 16H), 2.07-2.24 (m, lH), 2.81 (s, 6H), 2.99-3.19 (m, 4H), 3.98 (brs, 2H), 4.12 (s, lH), 5.46 (s, lH), 6.0l (d, J = 2.1 Hz, lH), 6.51 (dd, J-2.1, 8.0 Hz, lH), 6.92 (d, J = 8.l Hz, 2H), 7.41 (d, J = 7.8 Hz, 2H), 7.89 (d, J = 8.7 Hz, lH). HRMS. Calcd for C ₃₂ H ₅₀ N ₄ O ₄ S: 586.3552. Found (M + H): 587. 3620.

Example 1423

(4R-cis) -N- [5- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxido-1-benzothiepin-5-yl] phenoxy] pentyl] glycine

Step 1: Preparation of the pentyl azide intermediate

To the solution of the pentyl bromide intermediate (400 mg, 0.657 mmol) obtained in step 1 of Example 1420 in dimethyl sulfoxide (20 mL) was added sodium azide (47 mg, 0.723 mmol, 1.1 equiv) and the resulting transparent The solution was stirred at 23 ° C. for 16 h. The reaction solution was diluted with 100 mL of ethyl acetate and then washed with water (2 × 100 mL) and brine (1 × 100 mL). The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to yield 390 mg (quantitative) of the pentyl azide intermediate as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 0.82 -0.90 (m, 7H), 1.05-1.56 (m, 12H), 1.59-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J = 8.3 Hz, lH), 2.82 (s, 6H), 3.08 (q, 2H), 3.44 (t, J = 7.7 HZ, 2H), 3.99 (t, J = 7.7 Hz, 2H), 4.91 (br s, lH ), 5.47 (s, lH), 6.13 (d, J = 7.58 Hz, lH), 6.68 (d, J = 7.7 Hz, lH), 7.14 (ABq, 4H), 7.91 (d, J = 7.8 Hz, lH ).

Step 2: Preparation of Amino Ester Intermediates

The suspension of pentyl azide intermediate (390 mg, 0.684 mmol) and Pd / C 100 mg obtained in step 1 in ethanol (15 mL) was stirred for 4.5 h under a hydrogen gas atmosphere (48 psi). The ethanol suspension was filtered through celite and concentrated in vacuo to give a yellow oil. The oil was immediately diluted with acetonitrile (15 mL) and then triethylamine (0.156 g, 1.54 mmol, 2.25 equiv) and bromo acetic acid benzyl ester (0.212 g, 0.925 mmol, 1.35 equiv) were added. The reaction was stirred at 23 ° C. for 48 hours. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate (20 mL) and washed with water (2x20 mL) and brine (1x20). The organic layer was dried (MgSO ₄ ) and vacuum dried to yield 420 mg (89%) of amino ester intermediate as a yellow oil. ¹ H NMR (CDCl ₃ ) δ 0.82-0.90 (m, 6H), 1.05-1.56 (m, 14H), 1.58-1.71 (m, 3H), 1.78-2.01 (m, 4H), 2.20 (t, J = 8.3 Hz, 1H), 2.75 (d, J = 7.83 Hz, lH), 2.795 (s, 6H), 3.08 (q, 2H), 3.68-3.85 (m, 2H), 3.87-4.04 (m, 2H), 4.09 (s, 1H), 5.l47 (s, lH), 5.46 (s, lH), 5.98 (d, J = 7.58), 6.50 (dd, lH), 6.85-6.87 (m, 2H), 7.28- 7.45 (m, 5 H), 7.89 (d, J = 8.0 Hz, l H). MS (ES) m / e 693.

Step 3: Preparation of Acid

The suspension of benzyl ester intermediate obtained in step 2 (0.420 g, 0.61 mmol) and Pd / C 100 mg suspended in ethanol (15 mL) was stirred under hydrogen gas atmosphere (48 psi) for 16 h. This suspension was filtered through celite and concentrated in vacuo to yield 0.330 g of a yellow semisolid. The material was triturated with diethyl ether and the remaining semisolid was dried in vacuo to afford 0.19 g (52%) of the title compound as a yellow semisolid. ¹ H NMR (CDCl ₃ ) δ 0.86 (br s, 7H), 1.0-1.72 (m, 18H), 1.79 (br s, 2H), l.98 (s, 2H), 2.09-2.24 (m, 2H) , 2.78 (s, 6H), 2.99 (q, 2H), 3.96 (bs, 2H), 4.08 (S, lH), 5.46 (s, lH), 5.97 (s, lH), 6.40-6.49 (m, lH ), 7.14 (ABq, 4H), 7.85 (t, J = 7.93 Hz, lH). MS (ES) m / e 603.

Example 1424

(4R-cis) -4-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido -1-benzothiepin-5-yl] phenoxy] methyl] benzoic acid

Step 1: Preparation of the Benzoate Intermediate

Example 1402, 0.53 g (1.15 mmol) of 5- (4'-hydroxyphenyl) -7-dimethylamino) tetrahydrobenzothiene-1,1-dioxide obtained in step 10 was dissolved in 10 ml of dimethylformamide. To the solution was added 35 mg (1.39 mmol) of 95% sodium hydride and stirred for 10 minutes. 525 mg (2.29 mmol) of methyl 4- (bromomethyl) benzoate was added to the reaction mixture and stirred for 16 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and solvent evaporated to afford 0.51 g (73%) of benzoate intermediate. ¹ H NMR (CDCl ₃ ) δ 0.86-0.96 (m, 6H), 1.14 -1.47 (m, 10H), 1.60-1.64 (m, lH), 2.20-2.23 (m, lH), 2.80 (s, 6H) , 2.99 (d, J = 15.l Hz, lH), 3.15 (t, J = 15.l Hz, lH), 3.92 (s, 3H), 4.09-4.15 (m, lH), 5.17 (s, 2H ), 5.49 (s, lH), 5.94 (d, J = 2.2 Hz, lH), 6.50 (dd, J = 8.9, 2.6 Hz, lH), 7.00 (d, J = 8.7 Hz, 2H), 7.43 (d , J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.93 (d, J = 8.9 Hz, lH), 8.06 (d, J = 8.5 Hz, 2H).

Step 2: Preparation of Acid

0.51 g (0.84 mmol) of the benzoate intermediate obtained in step 1 and 325 mg (2.53 mmol) of KOSi (CH ₃ ) ₃ (Aldrich) were dissolved in 16 mL of THF, followed by stirring for 3.5 hours. THF was evaporated, water was added, extracted with ethyl acetate, then dried over magnesium sulfate, filtered and solvent evaporated to afford 0.30 g (60%) of the title compound as a white solid. mp 156-159 ° C; ¹ H NMR (CDCl ₃ ) δ 0.89-0.94 (m, 6H), 1.24-1.43 (m, 10H), 1.62-1.66 (m, lH), 2.20-2.24 (m, lH), 2.84 (s, 6H) , 3.02 (d, J = 15.l Hz, lH), 3.17 (d, J = l5.l Hz, lH), 4.14 (s, lH), 5.20 (s, 2H), 5.50 (s, lH), 6.16 (s, lH), 6.71 (d, J = 9.l Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.l Hz, 2H), 7.57 (d , J = 8.3 Hz, 2H), 7.95 (d, J = 8.9 Hz, lH), 8.13 (d, J = 8.l Hz, 2H). HRMS. Calcd for C ₃₄ H ₄₄ NO ₆ S: 594.2889. Found: 594.2913.

Example 1425

(4R-cis) -1-[[4-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1 -Dioxido-1-benzothiepin-5-yl] phenoxy] methyl] phenyl] methyl-pyridinium chloride

Step 1: Preparation of Chlorobenzyl Intermediates

Example 1402, 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (5.0 g, 10.9 mmol) obtained in step 10 was added to acetone (100 mL). The solution dissolved under N ₂ at 25 ° C. was treated with K ₂ CO ₃ powder (2.3 g, 16.3 mmol, 1.5 equiv) and α, α′-dichloro-p-xylene (6.7 g, 38.1 mmol, 3.5 equiv) to obtain The solution was stirred at 65 ° C. for 48 hours. The reaction mixture was cooled to 25 ° C. and concentrated to 1/5 of the original solution volume. The residue was dissolved in EtOAc (150 mL) and washed with water (2x150 mL). The aqueous layer was extracted with EtOAc (2 × 150 mL) and the organic extracts were combined and washed with saturated aqueous NaCl solution (2 × 150 mL). The combined extracts were dried (MgSO ₄ ) and concentrated in vacuo to afford a yellow oil.

Purification by flash chromatography (5.4 × 45 cm silica, 25-40% EtOAc / hexanes) gave chlorobenzyl intermediate (4.7 g, 72%) as a white foam. ¹ H NMR (CDCl ₃ ) δ 0.89-0.94 (m, 6H), 1.12 -1.48 (br m, 10H), 1.63 (m, lH), 2.22 (m,: lH), 2.81 (s, 6H), 3.05 (ABq, J = 15.l Hz, J = 50.0 Hz, 2H), 4.11 (d, J = 8.l Hz, lH), 4.60 (s, 2H), 5.11 (s, 2H), 5.48 (s, lH), 5.96 (d, J = 2.4 Hz, lH), 6.48 (dd, J = 8.9, 2.6 Hz, lH), 7.00 (d, J = 8.9 Hz, 2H), 7.36-7.47 (m, 5H), 7.85 (d, J = 8.9 Hz, lH).

Step 2: Preparation of the Quaternary Salt

The solution in which the chlorobenzyl intermediate (1.0 g, 1.7 mmol) obtained in step 1 was dissolved in acetonitrile (5 mL) at 25 ° C. N ₂ was treated with pyridine (5 mL) and stirred at 35 ° C. for 6 hours. The pale amber solution was cooled to 25 ° C. and concentrated in vacuo to afford the title compound (1.08 g, 96%) as a yellow solid. mp 154-156 ° C; ¹ H NMR (CDCl ₃ ) δ 0.83 (m,

6H), 1.06-1.44 (br m, 10H), 1.60 (m, lH), 2.13 (m, lH), 2.71 (s, 6H), 3.02 (ABq, J = 15.l Hz, J = 28.4 Hz, 2H), 4.09 (s, lH), 5.00 (s, 2H), 5.38 (s, lH), 5.91 (d, J = 2.4 Hz, lH), 6.26 (s, 2H), 6.41 (dd, J = 8.9 , 2.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 7.26 (m, lH), 7.40 (d, J = 7.7 Hz, 4H), 7.73 (d, J = 7.9 Hz, 2H), 7.78 (d, J = 8.9 Hz, 2H), 7.93 (t, J = 6.8 Hz, lH), 8.34 (t, J = 7.7 Hz, lH), 8.58 (br s, lH), 9.69 (d, J = 5.8 Hz, 2H); HRMS. Calcd for C ₃₉ H ₄₉ N ₂ O ₄ S: 641.3413. Found: 641.3425.

Example 1426

(4R-cis) -1-[[4-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1 -Dioxido-1-benzothiepin-5-yl] phenoxy] methyl] phenyl] methyl] -4-aza-1-azoniabicyclo [2.2.2] octane chloride

Under N ₂ , a solution of 8.7 g (14.5 mmol) of chlorobenzyl intermediate (prepared in a procedure similar to that outlined in Step 1) in 60 ml of acetonitrile was treated with diazabicyclo [2.2.2 at 35 ° C. ] 2.9 g (26.2 mmol) of octane (DABCO) were added dropwise over 30 minutes to a solution dissolved in 40 ml of acetonitrile. A colorless precipitate formed during the addition. The slurry was further stirred at 35 ° C. for 2 hours. The product was collected and washed with 1 L of acetonitrile to give 9.6 g (93%) of the title compound as a colorless crystalline solid. mp 223-230 ° C. (decomposition); ¹ H NMR (CDC1 ₃ ) δ 0.89 (m, 6H), 1.27-1.52 (br m, 10H), 1.63 (m, lH), 2.20 (m, lH), 2.8l (s, 6H), 3.06 (ABq , J = 15.l Hz, J = 43.3 Hz, 2H), 3.16 (s, 6H), 3.76 (s, 6H), 4.11 (d, J = 7.7 Hz, lH), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, lH), 5.96 (s, lH), 6.40 (d, J = 8.9 Hz, lH), 6.99 (d, J = 8.0 Hz, 2H), 7.26 (m, 1H) , 7.44 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.87 (d, J = 8.9 Hz, 1H); HRMS. Calcd for C ₄₀ H ₅₆ N ₃ O ₄ S: 674.3992. Found: 674.4005.

Example 1426a

(4R-cis) -1-[[4-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1 -Dioxido-1-benzothiepin-5-yl] phenoxy] methyl] phenyl] methyl] -4-aza-1-azoniabicyclo [2.2.2] octane chloride

Diazabicyclo [2.2.2] -octane (DABCO, 0.95) was prepared by dissolving the chlorobenzyl intermediate (4.6 g, 7.7 mmol) obtained in step 1 of Example 1425 in acetonitrile (100 mL) at 25 ° C. and N ₂ . g, 8.5 mmol, 1.1 equiv) and stirred at 35 ° C. for 2 h, at which time a white solid precipitated out. The white solid was collected, washed with CH ₃ CN and recrystallized from CH ₃ OH / Et ₂ O to give the title compound (4.95 g, 91%) as a white solid. mp223-230 ° C. (decomposition); ¹ H NMR (CDC1 ₃ ) δ0.89 (m, 6H), 1.27-1.52 (br m. 10H), 1.63 (m, lH), 2.20 (m, lH), 2.81 (s, 6H), 3.06 (ABq , J = 15.l Hz, J = 43.3 HZ, 2H), 3.16 (s, 6H), 3.76 (s, 6H), 4.11 (d, J = 7.7 Hz, lH), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, lH), 5.96 (s, lH), 6.49 (d, J = 8.9 Hz, lH), 6.99 (d, J = 8.0 Hz, 2H), 7.26 (m, lH) , 7.44 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.87 (d, J = 8.9 Hz, lH); HRMS. Calcd for C ₄₀ H ₅₆ N ₃ O ₄ S: 674.3992. Found: 674.4005.

Example 1427

(4R-cis) -N- (carboxymethyl) -N-[[4-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4 -Hydroxy-1,1-dioxido-1-benzothiepin-5-yl] phenoxy] methyl] phenyl] methyl] glycine

Step 1: Preparation of Chlorobenzyl Intermediates

5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzo obtained in Example 1402, step 10, in a solution of 144 mg (3.59 mmol, 60% dispersion) of NaH stirred in 29 mL of DMF. Thiefin-1,1-dioxide (1.5 g, 3.26 mmol) was added and the resulting solution was stirred at room temperature for 45 minutes. To this solution was added 7.13 g (40.75 mmol) of dichloro p-xylene and the mixture was stirred overnight. DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give chlorobenzyl intermediate. ¹ H NMR (CDC1 ₃ ) δ 0.90 (q, 6H), 1.05-1.65 (m, 11H), 2.2 (t, lH), 2.8 (s, 6H), 3.0 (q, 2H), 4.1 (d, 1H), 4.6 (s, 2H), 5.1 (s, 2H), 5.5 (s, lH), 6.0 (s, lH), 6.6 (d, lH), 7.0 (d, 2H), 7.4 (m, 6H ), 7.8 (d, lH).

Step 2: Preparation of Amino Diester

1.03 g (1.72 mmol) of chlorobenzyl intermediate, 1.63 g (8.6 mmol) of diethyl amino diacetate and 0.72 g (8.6 mmol) of NaHCO ₃ were added to 30 mL of DMF, and the mixture was stirred at 100 ° C. for 6 hours. The DMF was removed in vacuo and the residue was extracted with ether and washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give amino diester intermediate. ¹ H NMR (CDCl ₃ ) δ0.90 (q, 6H), 1.05-1.65 (m, l7H), 2.2 (t, lH), 2.8 (S, 6H), 3.0 (q, 2H), 3.55 (s, 4H), 3.95 (s, 2H), 4.1-4.2 (m, 5H), 5.05 (s, 2H), 5.42 (s, lH), 5.95 (s, lH), 6.5 (d, lH), 7.0 (d , 2H), 7.4 (s, 6H), 7.8 (d, lH).

Step 3: Preparation of Amino Diacid

The solution obtained by dissolving 0.863 g (1.15 mmol) of dibenzyl ester and 0.232 g (5.52 mmol) of LiOH in 30 mL of THF and 30 mL of water was stirred at 40 ° C. for ₂ hours under N ₂ . The reaction mixture was diluted with ether and washed with 1% HCl. The aqueous layer was extracted twice with ether, the extracts were combined, washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford the desired title compound as a solid. mp 175 ° C .; ¹ H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, llH), 2.22 (t, lH), 2.8 (s, 6H), 3.0 (t, 2H), 3.5 (s, 4H ), 3.9 (s, 2H), 4.1 (d, 1H), 5.1 (s, 2H), 5.4 (s, lH), 6.05 (s, lH), 6.5 (d, lH), 7.0 (d, 2H) , 7.4 (m, 6 H), 7.78 (d, l H). HRMS. Calcd for C ₃₈ H ₅₀ N ₂ 0 ₈ S: 695.3366. Found: 695.3359.

Elemental Analysis for C ₃₈ H ₅₀ N ₂ O ₈ S

Calculated: C, 65.68; H, 7. 25; N, 4.03; S, 4.61.

Found: C, 64.95; H, 7. 32; N, 3.94; S, 4.62.

Example 1428

(4R-cis) -4-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1 with trifluoroacetic acid , 1-dioxido-1,1-dioxido-1-benzothiepin-5-yl] phenoxy] methyl] -1-methylpyridinium salt (1: 1)

Step 1: Preparation of Picolinyl Intermediate

Example 1402, 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (12.0 g, 26.1 mmol) obtained in step 10 was stirred and dissolved in 200 mL of DMF. 1.4 g (60% oil dispersion, 35 mmol) of sodium hydride was added to the solution, and the reaction was stirred at room temperature for 1 hour. 5.99 g (36.5 mmol) of 4-picolyl chloride hydrochloride were treated with cold saturated NaHCO ₃ solution and extracted with diethyl ether. The ethereal extract was washed with brine, dried over MgSO ₄ and filtered. The reaction was cooled in an ice bath and a solution of 4-picolinyl chloride in diethyl ether was added. The reaction was stirred at room temperature for 17 hours. The reaction was quenched by addition of 25 mL saturated NH ₄ Cl solution, diluted with 600 mL ethyl acetate, washed with ₄ × 250 mL water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Silicagel chromatography (Waters-prep 500) purification using 60% ethyl acetate / hexanes provided 11.05 g (77%) of picolinyl intermediate as a colorless solid. mp 95-98 ° C .; ¹ H NMR (CDCl ₃ ) δ0.86-0.96 (m, 6H), 1.02-1.52 (m, 10H), 1.58-1.70 (m, lH), 2.16-2.29 (m, lH), 2.81 (s, 6H ), 3.07 (ABq, J _AB = 15.3, 49.6 Hz, 2H), 4.10 (d, J = 7.5 Hz, lH), 5.15 (s, 2H), 5.50 (s, lH), 5.94 (d, J = 2.7 Hz, lH), 6.51 (dd, J = 2.4, 8.7 Hz, lH), 7.00 (d, J = 9.0 Hz, 2H), 7.39 (d, 6.0 Hz, 2H), 7.44 (s, J = 8.7 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 8.63 (dd, J = 1.6,4.8 Hz, 2H).

Step 2: Preparation of the Quaternary Salt

To the solution of 0.41 g (0.74 mmol) of picolinyl intermediate obtained in step 1 in 10 ml of acetonitrile and 3 ml of dichloromethane, 137 mg (0.97 mmol) of iodomethane were added. The reaction was stirred at room temperature for 16 hours and then concentrated under nitrogen. Purification of reverse phase chromatography using 60-55% water / acetonitrile (Waters-Delta prep) provided 0.304 g (60%) of the title compound as a colorless solid. mp 96-99 ° C .; ¹ H NMR (CDCl ₃ ) δ0.85-0.95 (m, 6H), 1.03-1.52 (m, 10H), 1.57-l.70 (m, lH), 2.12-2.27 (m, lH), 2.84 (s , 6H), 3.09 (ABq, J _AB = 15.0, 27.9 HZ, 2H), 4.1l (S, lH), 4.46 (s, 3H), 5.37 (s, 2H), 5.50 (s, lH), 6.07 ( d, J = 2.4 Hz, lH), 6.61 (dd, J = 2.5, 8.7 Hz, lH), 7.02 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 7.2 Hz, 2H), 7.90 ( d, J = 8.7 Hz, lH), 8.14 (d, J = 6.3 Hz, 2H), 8.80 (d, J = 6.6 Hz, 2H). HRMS calcd for C ₃₃ H ₄₅ N ₂ O ₄ S: 565.3100. Found: 565.3125.

Example 1429

(4R-cis) -4-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido -1,1-dioxido-1-benzothiepin-5-yl] phenoxy] methyl] -1-methylpyridinium, methanesulfonate (salt)

1.56 g (14.6 mmol) of methanesulfonic acid methyl ester was added to a solution in which 6.5 g (11.8 mmol) of picolyl intermediate obtained in Step 1 of Example 1428 was stirred and dissolved in 140 mL of acetonitrile. Heated at 70 ° C. for 15 hours. The reaction was cooled and diluted with 50 ml of ethyl acetate. The resulting solid was collected by vacuum filtration to give 6.14 g (79%). The filtrate was concentrated in vacuo and the residue was crystallized from hot acetonitrile to give 1.09 g (14%). A total of 7.23 g (93%) of the title compound desired were obtained as off-white solid. mp 232 -233.5 ° C; ¹ H NMR (CDCl ₃ ) δ 0.66-0.76 (m, 6H), 0.85-0.95 (m, lH), 0.95-1.35 (m, 9H), 1.42-1.54 (m, lH), 1.95-2.22 (m , lH), 2.50 (s, lH), 2.56 (S, 3H), 2.63 (S, 6H), 2.9 l (ABq, J = 16.5, 24.0 Hz, 2H), 3.88 (s, lH), 4.40 (s , 3H), 5.2l (s, 3H), 5.78 (d, J = 2.4 Hz, lH), 6.31 (dd, J = 2.5, 8.7 Hz, lH), 6.84 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.7 Hz, lH), 8.0 (d, J = 6.6 Hz, 2H), 9. 02 (d, J = 6.6 Hz, 2H). HRMS calcd for C ₃₃ H ₄₅ N ₂ O ₄ S: 565.3100. Found: 656.3087.

Elemental Analysis for C ₃₃ H ₄₅ N ₂ O ₄ S

Calculated: C, 61.79; H, 7. 32; N, 4.24; S, 9.70.

Found: C, 61.38, H, 7.47; N, 4.22; S, 9.95.

Example 1430

(4R-cis) -4-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido -1,1-dioxido-1-benzothiepin-5-yl] phenoxy] methyl] -1-methylpyridinium, methanesulfonate (salt)

Step 1: Preparation of Picolinyl Chloride Intermediates

Example 1402, A solution of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiefin-1,1-dioxide (1 g, 2.1 mmol) obtained in step 10 in 50 ml of acetone To anhydrous K ₂ CO ₃ (0.45 g, 3.2 mmol), tetrabutylammonium iodide (0.1 g, 0.2 mmol) and 2,6-bischloromethylpyridine (1.2 g, 10.8 mmol) were added. The flask was equipped with a nitrogen gas adapter and a magnetic stirrer. The reaction was heated to reflux overnight. After 18 hours, the reaction was diluted with ether and washed with water and brine (30 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. Silicagel chromatography purification eluting with 25% EtOAc / hexanes gave 0.75 g (55%) of picolyl chloride intermediate as an oil (0.70 g, 55%). ¹ H NMR (CDCl ₃ ) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, lH), 2.14-2.24 (m, lH), 2.80 (s, 6H ) 3.05 (ABq, 2H), 4.10 (d, 2H), 4.65 (s, 2H), 5.20 (s, 2H), 5.45 (s, lH), 5.95 (s, lH), 6.50 (d, lH), 7.0 (d, 2H), 7.35-7.50 (m, 4H), 7.70-7.85 (m, 2H).

Step 2: Preparation of Pyridinyl Malonate Intermediate

A mixture of dibenzyl malonate (1.42 g, 5.01 mmol) added to DMF (20.0 mL) and sodium hydride (0.13 g, 3.3 mmol) was injected into a dry three neck flask. The flask was equipped with a nitrogen gas adapter and a magnetic stirrer. Picolyl chloride intermediate (1 g, 1.67 mmol) was added and heated at 90 ° C. overnight. The reaction was cooled, extracted with methylene chloride with 5% HCl and washed with water (25 mL) and brine (50 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was purified by C-28 reverse phase column eluting with 50% acetonitrile / water to give the pyridinyl malonate intermediate as a white foamy solid (1 g, 71%). ¹ H NMR (CDC1 ₃ ) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), l.56-1.66 (m, 1H), 2.14-2.24 (m, lH), 2.80 (s , 6H) 3.05 (ABq, 2H), 3.22 (d, 2H), 4.05 (d, lH), 4.16 (t, lH), 5.02 (s, 2H), 5.08 (s, 4H), 5.44 (s, lH ), 5.97 (s, lH), 6.96-7.l0 (m, 3H), 7.20-7.32 (m, l2H), 7.5 (t, lH), 7.9 (d, lH).

Step 3: Preparation of Pyridinyl Acid

The pyridinyl malonate intermediate (0.6 g, 0.7 mmol), THF / water (25.0 mL, 1: 1) and lithium hydroxide monohydrate (0.14 g, 3.4 mmol) obtained in step 2 were injected into a 100 mL round bottom flask. The reaction was stirred at room temperature overnight. After 18 hours, the reaction was extracted with 1% HCl and ether and then washed with water (20 mL) and brine (30 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to afford the desired title compound as a white solid (0.44 g, 90%). mp 105-107 ° C; ¹ H NMR (CDC1 ₃ ) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, lH), 2.14-2.24 (m, lH), 2.80 (s, 6H ), 3.05 (m, 2H), 3.10 (ABq, 2H), 3.22 (m, 2H), 4.05 (s, lH), 5.30 (s, 2H), 5.50 (s, lH), 5.97 (S, lH) , 6.50 (d, lH), 7.02 (d, 2H), 7.3 (d, lH), 7.42 (d, 2H), 7.58 (d, lH), 7.8-7.9 (m, 2H). HRMS. Calcd for C ₃₅ H ₄₆ N ₂ O ₆ S: 623.3155. Found: 623.3188.

Example 1431

(4R-cis) -4- (carboxymethyl) -N-[[6-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4 -Hydroxy-1,1-dioxydo-1-benzothiepin-5-yl] phenoxy] methyl] -2-pyridinyl] methyl] glycine

Step 1: Preparation of Pyridinyl Diester Intermediates

A mixture of diethyl aminodiacetate (8 g, 68 mmol) and sodium carbonate (0.63 g, 5.9 mmol) was treated with picolinyl chloride intermediate (0.72 g, 1.2 mmol, obtained in Example 1430, step 1) and 3 hours at 160 ° C. Treated during. The reaction was cooled, diluted with ether and washed with 1% HCl, water (25 mL) and brine (50 mL). The extracts were combined, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by evaporation on a Kugellor apparatus to give the pyridinyl diester intermediate as a yellowish effervescent solid (0.72 g, 80%). ¹ H NMR (CDC1 ₃ ) δ 0.84-0.95 (m, 6H), 1.02-1.5 (m, 16H), 1.56-1.66 (m, lH), 2.14-2.24 (m, 1H), 2.80 (s, 6H) 3.05 (ABq, 2H), 3.70 (s, 4H), 4.2-4.4 (m, 6H), 5.30 (s, 2H), 5.56 (s, lH), 6.02 (s, lH), 6.60 (d, lH) , 7.10 (d, 2H), 7.50 (m, 3H), 7.61 (d, lH), 7.80 (t, lH), 7. 95 (d, lH). HRMS. Calcd for C ₄₁ H ₅₇ N ₃ O ₈ S: 752.3945. Found: 752.3948.

Step 2: Preparation of Pyridinyl Diacid

A mixture of pyridine-aminodiacetate intermediate (0.7 g, 0.93 mmol, obtained in step 1) and lithium hydroxide monohydrate (0.18 g, 4.5 mmol) in THF / water (25.0 mL, 1: 1) was added at 40 ° C. Stir overnight (18 hours). The reaction mixture was diluted with ether and washed with 1% HCl, water (20 mL) and brine (30 mL). The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo to afford the desired title compound as a white solid (0.44 g, 90%). mp 153-155 ° C; ¹ H NMR (CDC1 ₃ ) δ0.84-0.95 (m, 6H), 1.02-1.5 (m, 10H), 1.56-1.66 (m, lH), 2.14-2.24 (m, lH), 2.80 (s, 6H ), 3.10 (ABq, 2H), 3.90 (m, 3H), 4.05 (s, lH), 4.40 (s, 2H), 5.20 (s, 2H), 5.50 (s, lH), 5.97 (s, lH) , 6.50 (d, lH), 7.02 (d, 2H), 7.3 (d, lH), 7.42 (d, 2H), 7.58 (d, lH), 7.8-7.9 (m, 2H) .HRMS. Calcd for C ₃₇ H ₄₉ N ₃ 0 ₈ S: 696.3319. Found: 696.3331.

Example 1432

(4R-cis)-[2- [2- [4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1- Dioxido-1-benzothiepin-5-yl] phenoxy] ethoxy] ethyl] propanediic acid

Step 1: Preparation of Bromoethyl Ether Intermediate

5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (a solution of 0.192 g (4.785 mmol, 60% dispersion) of NaH was stirred and dissolved in 28 ml of DMF). Example 1402, obtained in step 10) 2.0 g (4.35 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes. To this solution was added 13.2 g (54.38 mmol) of bis (2-bromoethyl) ether and stirred overnight at room temperature under N ₂ . DMF was removed in vacuo and the residue was extracted with ethyl acetate and washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give bromoethyl ether intermediate. ¹ H NMR (CDCl ₃ ) δ 0. 90 (q, 6h), l.05 -1.65 (m, 11H), 2.2 (t, lH), 2.8 (s, 6H), 3.0 (q, 2H), 3.5 (t, 2H), 3.9 (m, 4H), 4.1 (d, lH), 4.2 (d, 2H), 5.42 (s, lH), 5.95 (s, lH), 6.5 (d, lH), 6.95 (d, 2H), 7.4 (d, 2H ), 7.9 (d, lH).

Step 2: Preparation of Diester Intermediates

Dibenzyl malonate (Aldrich) 1.33 g (4.68 mmol) was added to a mixture of 94 mL of NaH (2.34 mmol, 60% dispersion) in 0 mL of THF and 15 mL of DMF, and the resulting solution was kept at room temperature for 15 minutes. After stirring, 0.95 g (1.56 mmol) of bromoethyl ether intermediate was added. The mixture was stirred at 80 ° C. overnight under N ₂ . The solvent was removed in vacuo and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give diester intermediate. ¹ H NMR (CDCl ₃ ) δ 0.90 (q, 6H), 1.05-1.65 (m, 11H), 2.2-2.3 (m, 3H), 2.8 (s, 6H), 3.0 (q, 2H), 3.6 ( t, 2H), 3.7 (m, 3H), 4.l (m, 3H), 5.l (s, 4H), 5.42 (s, 1H), 5.9 (s, 1H), 6.5 (d, 1H) 6.9 (d, 2H), 7.3 (m, 10H), 7.4 (d, 2H), 7.9 (d, 1H).

Step 3: Preparation of Diacid

0.761 g (0.935 mmol) of the diester intermediate obtained in step 2 and 35 mg of 10% Pd / C were suspended in 25 ml of ethanol and 5 ml of THF, and the mixture was shaken under 20 psi of hydrogen gas at room temperature for 2 hours. The catalyst was filtered off and the filtrate was concentrated to give the desired title compound as a solid. mp l19.5 ° C; ¹ H NMR (THF-d8) 0.95 (q, 6H), 1.05-1.65 (m, 1 lH), 2.1 (q, 2H), 2.25 (t, lH), 2.8 (s, 6H), 3.0 (t, 2H ), 3.47 (q, 2H), 3.58 (s, lH), 3.78 (t, 2H), 4.08 (d, lH), 4.15 (t, 2H), 5.4 (s, 1H), 6.05 (s, lH) , 6.55 (d, lH), 6.98 (d, 2H), 7.42 (d, 2H), 7. 8 (d, lH). HRMS. Calcd for C ₃₃ H ₄₇ NO ₉ S: 632.2893. Found: 632.2882.

Elemental Analysis for C ₃₃ H ₄₇ NO ₉ S

Calculated: C, 62.54; H, 7.47; N, 2.21; S, 5.06.

Found: C, 61.75; H, 7.56; N, 2.13; S, 4.92.

Example 1433

(4R-cis) -a-[[4- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido -1-benzothiepin-5-yl] phenoxy] methyl] -w-methoxypoly (oxy-1,2-ethanediyl)

Step 1: Preparation of Monomethyl PEG Mesylate Intermediate

To a solution of 20 g of monomethyl ether PEG dissolved in 100 ml of methylene chloride, 2.2 g (22 mmol) of triethylamine was added, and 2.5 g (22 mmol) of methanesulfonyl chloride was added dropwise to the resulting solution at 0 ° C. The resulting solution was stirred overnight at room temperature and triethyl amine hydrochloride was filtered off to provide the monomethyl PEG mesylate intermediate used in the next step without further purification and characterization.

Step 2: Preparation of Polyethylene Bonded Benzothiene

NaH 38 mg (1.52 mmol, 95%) and 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (obtained in Example 1402, step 10) 0.7 g (1.52 mmol) was added to 5.5 mL of DMF, and the mixture was stirred for 30 minutes under N ₂ at room temperature. To the solution was added 0.55 g (0.51 mmol) of the mesylate PEG intermediate (obtained in step 1) in 5.5 mL of DMF, and the resulting solution was stirred overnight under N ₂ at 50 ° C. The DMF was removed in vacuo and the residue was extracted with methylene chloride and washed with brine. The extract was dried over MgSO ₄ and the concentrated residue was purified by column chromatography to give the desired title compound as an oil. ¹ H NMR (CDC1 ₃ ) δ 0.9 (q, 6h), 1.05-1.65 (m, 11H), 2.2 (t, lH), 2.8 (s, 6H), 3.0 (q, 2H), 3.4 (s, 4H ), 3.5-3.85 (m, 95H), 4.1 (s, lH), 4.15 (t, 2H), 5.5 (s, lH), 6.05 (s, lH), 6.6 (d, lH), 6.9 (d, 2H), 7.4 (d, 2H), 7.9 (d, lH).

Example 1434

10 mL round bottom of 3-aminobenzothiene (0.380 g, 0.828 mmol), sodium hydroxide (0.35 mL, 0.875 mmol, 10% in H ₂ O) and toluene (0.50 mL) prepared in step 5 of Example 1398 It was injected into the flask. The reaction flask was purified by N ₂ , and equipped with a magnetic stirrer, and then cooled to 0 ° C. 3-chloropropyl chloroformate solution (1.440 g, 1.10 mmol, 12% in CH ₂ Cl ₂ / THF) was added. After 3.5 h, toluene (3.0 mL) was added and the mixture was washed with H ₂ O ( ₂ × ₄ mL), dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by silica gel flash chromatography using 20% EtOAc / hexane as eluent and concentrated in vacuo gave a white solid (0.269 g, 56%). ¹ H NMR (CDCl ₃ ) δ0.87-0.93 (m, 6H), 1.05-1.70 (m, llH), 2.14 (t, J = 6.3 Hz, 2H), 2.15-2.25 (m, lH), 2.81 ( s, 6H), 3.07 (ABq, 2H), 3.64 (t, J = 6.3 Hz, 2H), 4.11 (d, J = 7.5 Hz, 1H), 4.33 (t, J = 6.0 Hz, 2H), 5.50 ( s, lH), 5.99 (d, J = 2.4 Hz, lH), 6.51 (dd, J = 9.0, 2.7 Hz, lH), 6.65 (s, lH), 7.23 (d, J = 7.8 Hz, lH), 7.34-7.39 (m, 2H), 7.54 (d, J = 7.2 HZ, lH), 7.89 (d, 8.7 Hz, lH). HRMS (M + H). Calcd for C ₃₀ H ₄₄ N ₂ 0 ₅ SCl: 579. 2659. Found: 579.2691.

Example 1435

1,4-diazabicyclo (2.2.2) octane (0.0785 g, 0.700 mmol) and acetonitrile (1.0 mL) were mixed in a 10 mL round bottom flask. The reaction flask was purged with N ₂ , and equipped with a magnetic stirrer, and then heated to 37 ° C. A solution in which the product of Example 1434 (0.250 g, 0.432 mmol) was dissolved in acetonitrile (2.50 mL) was added. After 2.5 hours, 1,4-diazabicyclo (2.2.2) octane (0.0200 g, 0.178 mmol) was added. After 64 hours, 1,4-diazabicyclo (2.2.2) octane (0.0490 g, 0.437 mmol) was added. After 24 hours, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was dissolved in acetonitrile (2.0 mL) and precipitated with ethyl ether (10.0 mL). The precipitate was filtered off to give a white solid. This polishing process was repeated and then concentrated in vacuo to yield a white solid (0.185 g, 62%). mp 218.0-225.0 ° C; ¹ H NMR (CD ₃ OD) δ 0.90 (m, 6H), 1.05-1.55 (m, 1OH),

1.16 (t, J = 6.6 Hz, 2H), 1.78 (m, lH), 2.12 (m, 3H), 2.76 (s, 6H), 3.10 (m, 2H), 3.17 (t, J = 7.2 Hz, 6H ), 3.30-3.50 (m, 8H), 4.10 (s, lH), 4.21 (t, J = 5.4 Hz, 2H), 5.31 (s, lH), 6.10 (s, lH), 6.55 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 6.9 Hz, lH), 7.33-7.42 (m, 2H), 7.56 (s, 1H), 7.76 (d, J = 9.0 Hz, lH). HRMS. Calcd for C ₃₆ H ₅₅ N ₄ O ₅ SCl: 655.3893. Found: 655.3880.

Example 1436

Step 1.

3-chloromethylbenzoyl chloride (2.25 mL / 15.8 mmol) and acetone (8.0 mL) were mixed in a 25 mL round bottom flask. The reaction flask was cooled to 0 ° C. and an aqueous sodium azide solution (1.56 g / 24.0 mmol in 5.50 mL) was added. After 1.5 h, the reaction mixture was poured into ice water (80.0 mL), extracted with ethyl ether (2x25 mL), dried (MgSO ₄ ) and concentrated in vacuo to give a colorless oil (2.660 g, 86%). ¹ H NMR (CDCl ₃ ) δ4.62 (s, 2H), 7.47 (t, J = 7.8 Hz, lH), 7.99 (d, J = 7.8 Hz, lH), 7.99 (d, J = 7.8 Hz, 1H ), 8.05 (s, 1 H).

Step 2.

3-chloromethylbenzoyl azide (0.142 g, 0.726 mmol) and toluene (2.0 mL) were mixed in a 10 mL round bottom flask. The reaction flask was purged with N ₂ , and equipped with a magnetic stirrer and heated to 110 ° C. After 2 hours, the reaction mixture was cooled to room temperature and 3-aminobenzothiefine (0.365 g, 0.796 mmol) prepared in step 5 of Example 1398 was added. After 2.25 hours, the mixture was heated to 50 ° C. After 0.75 h, 3-chloromethylbenzoyl azide (0.025 g, 0.128 mmol) was added and the reaction mixture was cooled to room temperature and then concentrated in vacuo. Purification by silica gel flash chromatography using 20-30% EtOAc / nucleic acid as eluent and concentration in vacuo gave a white effervescent solid (0.309 g, 62%). ¹ H NMR (CDC1 ₃ ) δ 0.7l (t, J = 5.4 Hz, 3H), 0.88 (t, J = 6.3 Hz, 3H), l.03-1.60 (m, llH), 1.85 (d, 6.3 Hz , lH), 2.27 (m, lH), 2.76 (s, 6H), 3.15 (t, 2H), 4.17 (d, J = 6.6 Hz, lH), 4.48 (s, 2H), 5.42 (s, lH) , 6.07 (s, lH), 6.99 (d, J = 7.5 Hz), 7.18-7.26 (m, 2H), 7.30-7.41 (m, 3H), 7.63 (s, lH), 7.86 (d, J = 9.0 Hz, 2H), 7.96 (s, lH), 8.17 (s, lH). HRMS (M + Li). Calcd for C ₃₄ H ₄₄ N ₃ 0 ₄ SClLi: 632.2901. Found: 632.2889.

Example 1437

1,4-diazabicyclo (2.2.2) octane (0.157 g, 1.40 mmol) and acetonitrile (1.00 mL) were mixed in a 10 mL round bottom flask. The reaction flask was purified by N ₂ and equipped with a magnetic stirrer. A solution in which the product of Example 1436 (0.262 g, 0.418 mmol) was dissolved in acetonitrile (2.70 mL) was added. After 2.5 hours, a white precipitate formed. Ethyl ether (6.0 mL) was added and the precipitate was filtered off, washed with ethyl ether and dried in vacuo to afford a white solid (0.250 g, 80%). mp 246.0-248.0 ° C; ¹ H NMR (CD ₃ OD) δ 0.88 (m, 6H), 1.03-1.55 (m, 10H), l.76 (m, lH), 2.11 (m, lH), 2.74 (s, 6H), 3. l1 (m, 8H), 3.37 (m, 6H), 4.12 (s, lH), 4.39 (s, 2H), 5.3l (s, lH), 6.1l (S, lH), 6.52 (dd, J = 8.7, l.8 Hz, lH), 7.09 (d, J = 7.2 Hz, lH), 7.33 (d, J = 6.9 Hz, lH), 7.32-7.38 (m, 2H), 7.47 (m, 2H), 7.58 (s, lH), 7.73 (d, J = 8.7 Hz, 2H). HRMS. Calcd for C ₄₀ H ₅₆ N ₅ 0 ₄ SCl: 702.4053. Found: 702.4064.

Elemental Analysis for C ₄₀ H ₅₆ N ₅ O ₄ SCl

Calculated: C, 65.06; H, 7. 64; N, 9.48; S, 4.34; C1, 4.80.

Found: C, 64.90; H, 7.77; N, 9.42; S, 4.16; C1, 4.89.

Examples 1438-1454

The compounds of Examples 1438-1454 can be prepared using one or more of the synthetic schemes disclosed herein or using methods known to those skilled in the art.

Example 1455

3-Aminobenzothiene (0.0165 g / 0.0360 mmol), M-NCO-5000 (0.150 g / 0.30 mmol) obtained in step 5 of Example 1398 (methoxy-PEG-NCO, MW 5000, 35801 South, Alabama, USA Sheawater Polymers Inc., West Huntsville Memorial Parkway 2130) and CDCl ₃ (0.7 mL) were injected into 8 mm NMR tubes. This tube was clarified with N ₂ and after 72 hours the reaction mixture was heated to 50 ° C. After 24 hours, an additional amount of 3-aminobenzothiene (0.0077 g / 0.017 mmol) obtained in step 5 of Example 1398 was further added. After 24 hours, the reaction mixture was transferred to 2 ml vials and evaporated to dryness with N ₂ purification. The resulting white solid was dissolved in hot ethyl ether (2.0 mL) and ethyl acetate (0.057 mL / 4 drop), then cooled to precipitate and filtered. This precipitation procedure was repeated until no starting material was detected in the precipitate (TLC: SiO ₂ /80% EtOAc / hexanes). Concentration in vacuo gave a white solid (0.0838 g / 51%). ¹ H NMR (CDC1 ₃ ) δ0.82 -0.90 (m, 6H), 1.05-1.49 (m, 14H), 1.18 (t, J = 6.8 Hz, 2H), 1.59 (bt, lH), 2.18 (bt, lH), 2.34 (s, 2H), 2.78 (s, 6H), 3.04 (ABq, 2H), 3.35-3.80 (m, 625H), 4.09 (d, J = 7.2 Hz, 2H), 5.42 (s, lH ), 5.78 (s, lH), 6.04 (d, J = 1.6 Hz, lH), 6.47 (dd, J = 6.4, 3.2 Hz, lH), 7.07 (d, J = 7.6 Hz, lH), 7.31 (bs , lH), 7.60 (d, J = 7.6 H2, lH), 7.66 (s, lH), 7.85 (d, J = 8.8 Hz, lH). Mass spectrometer data also demonstrated the desired product.

Example 1456

5-R- [4- (2-bromoethoxyethoxy) phenyl-3,3-dibutyl-7-dimethylamino-4-R-hydroxybenzothiene-1,1-dioxide (Example 32, Step 1) A mixture of 0.845 g (10.7 mmol), 11.45 g diethyl iminodiacetate and 1.14 g sodium carbonate was maintained at 160 ° C. for 3.5 hours, diluted with brine and extracted with CH ₂ Cl ₂ . The CH ₂ Cl ₂ layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was distilled by cogelol at 120 ° C. under 0.5 torr to remove excess diethyl iminodiacetate to obtain 1.0 g of residue. The residue and a mixture of 0.8 g of lithium hydroxide, 25 ml of tetrahydrofuran and 25 ml of water were maintained at 45 ° C. for 3 days and concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous solution was diluted with 25 mL of water, acidified to pH 2 and extracted with CH ₂ Cl ₂ ( ₂ × 50 mL). The CH ₂ Cl ₂ layer was dried (MgSO ₄ ) and concentrated in vacuo. The residual solid was dissolved in hot CH ₂ Cl ₂ and ground with ether. The precipitate was collected to give 0.86 g of solid. MS (negative FAB), m / e 685 ( M + + Na).

Example 1457

500 mg (1.09 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1-dioxide (obtained in Example 1402, step 10) 5 ml of dimethylformamide The solution dissolved in was added via syringe to a solution in which 36% (1.41 mmol) of 95% NaH (1.41 mmol) was stirred and dissolved in 5 ml of dimethylformamide at −10 ° C. in an acetone-dry ice bath. The lump was stirred at −10 ° C. for 30 minutes. Then, a solution in which 1.25 g of 1,5-dibromopentane (5.45 mmol) was dissolved in 5 ml of dimethylformamide was added. The mixture was further stirred at −10 ° C. for 30 minutes, warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with water at 0 ° C. and extracted with ethyl acetate. The ethyl acetate layer was dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by silica gel column chromatography using 15% ethyl acetate / hexane as eluent to afford 470 mg (71%) of the titled bromide intermediate as a white solid. ¹ H NMR (CDC1 ₃ ) δ 0.91 (m, 6H), 1.20-1.67 (m, 13H), l.80 -2.00 (m, 4H), 2.22 (m, lH), 2.82 (s, 6H), 3.08 (Abq, 2 H). 3.46 (t, J = 6.9 Hz, 2H), 4.00 (t, J = 6.3 Hz, 2H), 4.1 (s, lH), 5.49 (s, lH), 6.00 (d, J = 2.4 Hz, lH), 6.52 (dd, J = 9.0 Hz, 2.7 Hz, lH), 6.92 (d, J = 8.7 Hz, 2H), 7.4 l (d, J = 8.7 Hz, 2H), 7.90 (d, J = 8.7 Hz, lH ).

A solution of 400 mg (0.66 mmol) of the bromide intermediate in stirring and dissolving in 2 ml of tris (trimethylsilyl) phosphite was refluxed at 100 ° C. overnight. The reaction mixture was cooled to room temperature and 30 mL of 50% methanol / water solution was added. The mixture was stirred at rt for 5 h. Then, it was concentrated in vacuo and the resulting aqueous solution was extracted with CH ₂ Cl ₂ . This CH ₂ Cl ₂ solution was dried over MgSO ₄ and concentrated in vacuo to give a yellowish oil. This oil was dissolved in CH ₂ Cl ₂ and triturated with ethyl acetate to give 202 mg (50%) of the desired product as a white solid. ¹ H NMR (CDC1 ₃ ) δ 0.90 (m, 6H), 1.14-2.10 (m, 21H), 2.81 (s, 6H), 3.07 (ABq, 2H), 3.98 (m, 3H), 4.11 (s, lH ), 5.48 (s, lH), 6.02 (d, J = 2.4 Hz, lH), 6.53 (dd, J = 8.9 Hz, 2.6 Hz, lH), 6.91 (d, J = 8.l Hz, 2H), 7.40 (d, J = 8.l Hz, 2H), 7.89 (d, J = 8.4 Hz, lH).

Example 1458

A mixture of 0.325 g (1.78 mmol) of 5-mercaptotetrazol acetate sodium salt, 1.0 g of potassium carbonate and 30 ml of dimethylformamide was stirred for 2 hours, and then 5-R- [4- (5-bromophene). 1.06 g (1.74 mmol) of methoxy) phenyl-3,3-dibutyl-7-dimethylamino-4-R-hydroxybenzothiene-1,1-dioxide (Example 1413, step 1) was added. The reaction mixture was stirred at rt for 20 h and concentrated in vacuo. The residue was taken up in ether and water (100 mL each) and stirred. A waxy substance was obtained which was insoluble in both the ether layer and the aqueous layer. This wax material was combined with the aqueous layer, acidified with concentrated HCl and extracted with CH ₂ Cl ₂ . The CH ₂ Cl ₂ layer was dried (MgSO ₄ ) and concentrated in vacuo to give 1.35 g of syrup. MS (negative FAB), m / e 686 (M ⁺ -1); NMR (CDCl ₃ ), 8.0 (d, lH, 7 Hz), 7.50 (d, 2H, 7 HZ), 7.00 (d, 2H, 7 Hz), 6.7 (d, 1H, 7 Hz), 6.2 (s, lH ), 5.6 (s, lH), 5.15 (s, 2H), 4.2 (s, lH), 4.1 (s, 2H), 3.7 (s, 2H), 3.1-3.2 (ABq, 2H), 2.9 (s, 6H), 2.3 (t, 2H, 8 Hz), 0.9-2.0 (m, 24H).

Example 1459

(4R-cis) -1- [N- [3- [3,3-dibutyl-7- (dimethylamino) -2,3,4,5-tetrahydro-4-hydroxy-1,1-di Oxido-1-benzothiepin-5-yl]] phenylacetamido] -4-aza-1-azoniabicyclo [2.2.2] octane chloride

Example 1398, aniline derivative (1.0 g, 2.2 mmol) prepared in step 5 was dissolved in dichloromethane (10 mL) at 0 ℃, N ₂ N, N-di-isopropyl-ethylamine (0.53 mL , 3.1 mmol, 1.4 equiv), followed by dropwise addition of chloroacetyl chloride (0.21 mL, 2.6 mmol, 1.2 equiv) over 10 minutes. This reaction mixture was stirred and heated up at 25 degreeC over 2 hours. The mixture was quenched by addition of 1N HCl (25 mL) and the aqueous layer was extracted with ethyl acetate (2 × 25 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (2 × 25 mL) and brine (30 mL), dried (MgSO ₄ ) and concentrated to yield a pale yellow oil that crystallized upon standing. The white crystals were collected and washed with hexane (50 mL) to give chloroacetyl intermediate (0.74 g, 63%) as a pale yellow solid. ¹ H NMR (CDC1 ₃ ) δ 0.95 (m, 6H), 1.15-l.7 l (br m, 11H), 2.24 (m, lH), 2.85 (s, 6H), 3.12 (ABq, J = 15.0 Hz , J = 48.8 Hz, 2H), 4.15 (d, J = 6.2 Hz, lH), 4.23 (s, 2H), 5.57 (s, lH), 6.05 (m, lH), 6.58 (dd, J = 8.9, 2.4 Hz, lH), 7.37-7.49 (m, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.9 Hz, lH), 8.30 (s, lH).

A solution of chloroacetyl intermediate (26 mg, 0.05 mmol) in acetonitrile (1 mL) at 50 ° C. and N ₂ was dissolved in diazabicyclo [2.2.2] octane (DABCO, 10 mg, 0.09 mmol, 1.8 equivalents). Treated and stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to 25 ° C. and concentrated to give a residue. This residue was dissolved in warm acetonitrile and tert-butyl methyl ether was added. This mixture was allowed to stand overnight, during which time crystals formed. The resulting white solid was collected and washed with tert-butyl methyl ether (25 mL) to give the title compound (17 mg, 55%) as a white crystalline solid. ¹ H NMR (CDCl ₃ ) δ0.88 (m, 6H), l.08-1.42 (br m, 8H), 1.45-1.80 (br m, 4H), 2.14 (m, lH), 2.75 (s, 6H ), 3.08 (ABq, J = 15.l Hz, J = 34.3 Hz, 2H), 3.21 (m, 6H), 3.79 (m, 6H), 4.12 (s, lH), 4.62 (s, 2H), 5.4 l (s, lH), 5.99 (m, 1H), 6.48 (d, J = 8.9 Hz, lH), 7.33 (m, lH), 7.70 (brs, lH), 7.87 (d, J = 8.6 Hz, lH ), 7.93 (s, lH), 11.3 (s, lH); HRMS. Calcd for C ₃₄ H ₅₁ N ₄ O ₄ S: 611.3631. Found: 611.3638.

Example 1460

Step 1: Preparation of diethyl iminodiacetateto-sulfonamoyl chloride

Sulfuryl chloride (27.552 g / 204.1 mmol) and chloroform (50.0 mL) were injected into a 250 mL round bottom flask. The reaction flask was purged with N ₂ , and equipped with a magnetic stirrer, and cooled to 0 ° C. A solution of diethyl iminodiacetate (18.902 g / 99,9 mmol) and triethylamine (10.112 g / 99.9 mmol) was added dropwise while maintaining the temperature at 20 ° C or lower. After complete addition, the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was poured into ice water (100 mL) and mixed well. The organic layer was separated, washed with 10% aqueous HCl solution (50 mL) and cooling water (2 × 50 mL), dried (CaCl ₂ ), filtered and concentrated in vacuo to give an amber liquid (5.706 g / 20%). ¹ H NMR (CDCl ₃ ) δ 1.30 (t, 6H), 4.23 (q, 4H), 4.38 (s, 4H). HRMS (EI / M + H). Calcd for C ₈ H ₁₅ NO ₆ SCl: 288.0309. Found: 288.0300.

Step 2:

Example 1398, 3-aminobenzothiefine (0.503 g / 1.097 mmol) described in Step 5, toluene (5.00 mL), diisopropylethylamine (0.148 g / 1.148 mmol) and the di prepared in Step 1 of this Example Ethyl iminodiacetateto-sulfonamoyl chloride (0.650 g / 2.260 mmol) was injected into a 25 mL round bottom flask. The reaction flask was purified by N ₂ and equipped with a magnetic stirrer. After 18 hours, diisopropylethylamine (0.074 g / 0.574 mmol) and diethyl iminodiacetateto-sulfonamoyl chloride (0.181 g / 0.628 mmol) were added. After 24 hours, dichloromethane (75.0 mL) was added. The mixture was washed with aqueous NaHCO ₃ solution (25.0 mL), aqueous NaCl solution (25.0 mL), dried (MgSO ₄ ) and concentrated in vacuo. Purified by silica gel flash chromatography using 30% ethyl acetate / hexane as eluent and concentrated in vacuo to yield a white solid (0.349 g / 45%). ¹ H NMR (CDCl ₃ ) δ 0.91 (m, 6H), 1.10-1.70 (m, 10H), 1.27 (t, J = 7.2 Hz, 6H), 1.90 (m, lH), 2.21 (m, lH) , 2.81 (s, 6H), 3.09 (dd, J = 36.6, 15.3 Hz, 2H), 4.11-4.24 (m, 9H), 5.50 (s, lH), 5.99 (d, J = 2.4 Hz, lH), 6.51 (dd, J = 8.7, 2.4 Hz, lH), 7.24-7.38 (m, 5H), 7.44 (bs, lH), 7.90 (d, J = 9.0 Hz, lH). HRMS (ESI / M + H). Calcd for C ₃₄ H ₅₂ N ₃ 0 ₉ S ₂ : 710.3145. Found: 710.3158.

Step 3: Preparation of the title compound

Benzothiene (0.224 g / 0.316 mmol) and tetrahydrofuran (1.00 mL) prepared in step 2 of this example were injected into a 10 mL round bottom flask. The reaction flask was purged with N ₂ and equipped with a magnetic stirrer. A solution in which LiOH.H ₂ O (0.030 g / 0.715 mmol) was dissolved in water (0.50 mL) was added. After 4 h, further LiOH.H ₂ O (0.015 g / 0.357 mmol) was added. After 30 minutes, water (6.0 mL) was added. The aqueous mixture was washed with diethyl ether (4x4.0 mL) and acidified with 3.0N HCl aqueous solution (0.40 mL). After 18 hours a white precipitate formed which was filtered off, washed with water (2.0 mL) and concentrated in vacuo. Precipitation from acetonitrile / diethylether / hexanes and recrystallization from t-butyl methyl ether / diethyl ether gave a white crystalline solid (0.109 g / 53%). ¹ H NMR (CD ₃ OD) δ 0.89 (m, 6H), 1.05-1.50 (m, 10H), 1.68 (m, lH), 2.16 (m, lH), 2.89 (s, 6H), 3.l3 ( m, 2H), 4.07 (s, 4H), 4.18 (s, lH), 5.45 (s, lH), 6.52 (s, lH), 6.93

(d, J = 8.7 Hz, lH), 7.19 (d, J = 6.6 Hz, lH), 7.35 (m, 3H), 7.70 (bs, lH), 7.99 (d, J = 8.7 HZ, lH). HRMS (ESI / M + H). C ₃₀ H ₄₄ N ₃ 0 ₉ S ₂ calcd: 654.2519. Found: 654.2512.

As will be apparent to those skilled in the art, where non-enantioselective synthesis is used in the above examples and a high concentration of the enantiomer is required, the chiral chromatographic purification in the appropriate synthesis step results in a high concentration of the enantiomer. The product can be obtained. For example, the synthesis proceeds via intermediate 5- (4'-methoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiefin-1,1-dioxide, followed by demethylation to yield intermediate 5- (4'- 5- (4'-methoxyphenyl) -7- (dimethylamino) tetrahydrobenzothier when forming hydroxyphenyl) -7- (dimethylamino) -tetrahydrobenzothiefine-1,1-dioxide Preference is given to a chiral chromatography purification step prior to demethylation of the pin-1,1-dioxide. Demethylation of the isolated enantiomer is then carried out in the next synthetic step, where the high concentration of the enantiomer is 5- (4'-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1 -Dioxide is obtained. As another example, chiral chromatography purification was performed immediately before step 7 of Example 1398a using a column such as a Chiralpak AD column with a mobile phase of ethanol / heptane (5-10% ethanol v / v) and at a wavelength of 220 nm. can do. The separated enantiomers can then be used as intermediates in synthesis step 6 to produce a final product with high concentration of enantiomers.

Similarly, the synthesis proceeded through intermediate 5- (3'-methoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiefin-1,1-dioxide, followed by demethylation to yield intermediate 5- (3'-hydrate). 5- (3'-methoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiefine when forming oxyphenyl) -7- (dimethylamino) -tetrahydrobenzothiefine-1,1-dioxide Preference is given to a chiral chromatography purification step prior to demethylation of the -1,1-dioxide. Demethylation of the isolated enantiomers is then carried out in the next synthetic step, where the high concentration of the enantiomers is 5- (3′-hydroxyphenyl) -7- (dimethylamino) tetrahydrobenzothiene-1,1 -Dioxide is obtained. As another example, chiral chromatography purification can then be performed immediately before step 8 of Example 1400 with the separated enantiomers used as intermediates in step 9 of the synthesis, resulting in high concentrations of the enantiomers in the final product. Can be obtained.

In addition, chiral chromatography purification used intermediate 5- (3 'or 4'-aminophenyl) -7- (dimethylamino) tetrahydro-benzothiene-1,1-dioxide as in the example corresponding to Scheme XII. It can be used when proceeding with synthesis. For example, intermediate 5- (3 'or 4'-aminophenyl) -7- (dimethylamino) tetrahydrobenzothiene-1 with high concentrations of the enantiomers is carried out immediately after step 5 of the example corresponding to Scheme XII. , 1-dioxide can be produced, which can be used in the next step of the synthesis.

Alternatively, using enantioselective synthesis (e.g., the method described in Example 1461 below), 5- (3 'or 4'-aminophenyl) -7- (dimethylamino) tetrahydro having a high concentration of the desired enantiomer Benzothiene-1,1-dioxide intermediates can be obtained,

Example 1461

Step 1: Preparation of Triple Intermediates

10.17 g (22.13 mmol) of 5- (4'-hydroxyphenyl) -7- (dimethylamino) -tetrahydrobenzothiene-1,1-dioxide (prepared in step 7 of Example 1398a) under 0 ° C. nitrogen gas Was dissolved in pyridine (42 mL) dropwise with triflic anhydride (4.1 mL, 24.4 mmol, 1.1 equiv). Once the addition was complete, it was taken out of the bath and the reaction stirred at room temperature for 21 hours. Pyridine was removed in vacuo, and the remaining oil was dissolved in water (100 mL) and extracted three times with ethyl acetate (45 mL each). The combined organic extracts were washed with 2N HCl (100 mL), 10% CuSO ₄ (100 mL) and brine (100 mL), then dried over MgSO ₄ , filtered and solvent evaporated. The residue was purified by silica gel chromatography (25% ethyl acetate in hexanes) to afford the title compound as pale yellow foam (11.42 g, 87.2%). ¹ H NMR (CD ₃ OD) δ 0.85-1.0 (m, 6H), 1.0-1.l5 (m, l0H), 1.76 (t, J = 12.6 Hz, l H), 2.12 (t, J = 13 Hz , lH), 2.79 (s, 6H), 3.1-3.2 (q _AB , 2H), 4.05 (S, lH), 5.42 (s, lH), 5.88 (d, J = 2.l Hz, lH), 6.59 (dd, J = 8.9, 2.l Hz, lH), 7.35 (d, J = 7.8 Hz, lH), 7.49 (d, J = 7.8 Hz, lH), 7.57 (t, J = 7.8 Hz, lH) , 7.66 (s, lH), 7.77 (d, J = 8.9 Hz, lH).

Step 2: Preparation of Immigration

Triflate (prepared in step 1) 11.41 g (19.28 mmol), palladium (II) acetate (433 mg, 1.93 mmol, 10 mol%), racemic 2,2'-bis- (biphenylphosphphenyl) -1, 6.6 mL of benzophenone imine (39.4 mmol, 2.0) in a solution of 1'-vinaptyl (1.41 g, 2.26 mmol, 12 mol%) and cesium carbonate (8.86 g, 27.2 mmol, 2.0 equiv) dissolved in 114 mL of tetrahydrofuran Equivalent)) was added. The mixture was stirred at reflux for 4 hours, filtered through celite and the solvent was removed in vacuo to yield 19.11 g of deep red foam. ¹ H NMR (CD ₃ OD) δ 0.8-1.45 (m, 16H), 1.6-1.75 (m, lH), 1.9-2.05 (m, l H), 2.78 (s, 6H), 2.98-3.l5 (q _AB , 2H), 3.88 (s, 1H), 5.17 (s, lH), 5.92 (d, J = 2.2 Hz, lH), 6.54 (dd, J = 9.1, 2.7 Hz, lH), 6.74 (d , J = 8.l Hz, lH), 6.80 (br s, lH), 7.0-7.12 (m, 2H), 7.15-7.25 (m, 3H), 7.35-7.52 (m, 7H), 7.52-7.68 ( m, 2H), 7.71 (d, J = 7.9 Hz, lH).

Step 3: Preparation of Aniline

Sodium acetate (6.33 g, 77.2 mmol, 4 equivalents) and hydroxylamine hydrochloride (4.02 g,) were dissolved in a solution of 19.1 g (19.3 mmol) of crude imine (prepared in Step 2) in methanol (200 mL). 57.9 mmol, 3 equiv) was added. After stirring for 1 hour, 1N sodium hydroxide (100 mL) was added and the mixture was extracted with methylene chloride (2x100 mL, 1x50 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO ₄ , filtered and solvent evaporated. The residue was purified by silica gel chromatography (50% ethyl acetate in hexanes) to afford the desired title compound as a yellow foam (8.64 g, 97.9%). ¹ H NMR (CD ₃ OD) δ0.86-0.97 (m, 6H), 1.07-1.52 (m, 10H), 1.76 (t, J = l2.6 Hz, l H), 2.10 (t, J = 11.5 Hz, lH), 2.79 (s, 6H), 3.05-3.18 (q _AB , 2H), 4.10 (s, lH), 5.22 (s, 1H), 6.19 (s, lH), 6.54 (dd, J = 8.9 , 1.9 Hz, lH), 6.68 (d, J = 8 Hz, lH), 6.82 (s, lH), 6.86 (d, J = 7.2 Hz, lH), 7.14 (t, J = 7.8 Hz, lH), 7.73 (d, J = 8.9 Hz, lH).

Biological analysis

The usefulness of the compounds described in the present invention was demonstrated by the following analysis. These assays were carried out in vitro and in animal models using procedures known to be able to prove the utility of the invention in practice.

In H14 cells [ ¹⁴ In vitro analysis of compounds that inhibit IBAT mediated absorption of C] -tauurocholate (TC)

Young hamster kidney cells (BHK) transfected with cDNA of human IBAT (H14 cells) were seeded at a concentration of 60,000 cells / well in a 96 well top count tissue culture plate for analysis that proceeded within 24 hours of inoculation, 48 30,000 cells / well were seeded for assays running within hours and 10,000 cells / well for assays running within 72 hours.

On day 1 of analysis, cell monolayers were washed gently once with 100 μl of assay buffer (Dulbecco's Modified Eagle's Medium + 4.5 g / L glucose + 0.2% (w / v) fatty acid depleted bovine serum albumin (FAF) BSA). To each well 50 μl of test compound of 2-fold concentrate added in Assay Buffer was added together with 50 μl of 6 μM [ ¹⁴ C] -tauurocholate in Assay Buffer (final concentration reached 3 μM). The cell culture plate was incubated at 37 ° C. for 2 hours, and then each well was gently washed twice with 100 μl of 4 ° C. Dulbecco Phosphate Buffered Saline (PBS) containing 0.2% (w / v) (FAF) BSA. It was. Then, wash gently once with 100 μl of 4 ° C. PBS without adding (FAF) BSA. 200 µl each of the liquid scintillation counting liquid was added, the plate was heat sealed, shaken at room temperature for 30 minutes, and the amount of radioactivity of each well was measured using a Packard top counter.

[ ¹⁴ C] -In vitro assay of compounds that inhibit uptake of alanine

This alanine uptake assay was performed in the same manner as the taurocholate assay, except that labeled alanine was used instead of labeled taurocholate.

[ ¹⁴ In vivo analysis of compounds inhibiting C] -tauurocholate from being absorbed into bile by rat ileum

[Metabolism of 3α, 7β-dihydroxy-7α-methyl-5β-cholanoic acid and 3α, 7β-dihydroxy-7α-methyl-5β-cholanoic acid in hamsters "in Biochimica et Biophysica Acta 833 (1985) 196-202 by See Une et al.

Male Vista rats (200-300 g) were anesthetized with inactin @ 100 mg / kg. A 10 "long PE10 tube was inserted into the bile duct. The small intestine was exposed and left on the gauze pad. A cannula (1/8" luer lock, tapered female adapter) was placed 12 cm from the junction of the small intestine and the cecum. Inserted. A gap was made at the position of 4 cm at the junction (8 cm at the venue). 20 ml of warm Dulbecco's phosphate buffered saline pH 6.5 (PBS) was used to wash the intestinal segments. A 20 cm long silicone tube (inner diameter 0.02 "x outer diameter 0.037") was inserted in the terminal gap. The peristaltic pump was hung on the adjacent cannula and the intestine was washed with warmed PBS at a rate of 0.25 ml / min for 20 minutes. The temperature of the long segment was continuously monitored. At the start of the experiment, 2.0 ml of the control sample ([ ¹⁴ C] -tauurocholate @ 0.05 mi / ml + 5 mM cold taurocholate) was loaded into the intestinal segment using a 3 ml syringe and the bile samples began to be collected. Control samples were injected for 21 minutes at a rate of 0.25 ml / min. Bile sample fractions were collected every 3 minutes during the 27 minutes of the experiment. After 21 minutes of sample injection, the ileal loops were washed with 20 ml of warmed PBS (using a 30 ml syringe) and then the loops were washed at a rate of 0.25 ml / min for 21 minutes with warmed PBS. The second perfusion was initiated as described above, but in this case the test compound was administered (21 minutes of washing followed by 21 minutes of washing), and bile was collected every 3 minutes for 27 minutes of initiation. If necessary, as described above, generally, third perfusion including the control sample may be performed.

Measurement of Liver Cholesterol Concentration (Liver CHOL)

Liver tissue was weighed and homogenized in chloroform: methanol (2: 1). After homogenization and centrifugation, the supernatant was separated and separated under nitrogen. The residue is dissolved in isopropanol and allain, C.A., et al. (1974) Clin. Chem. 20, 470], the cholesterol content was measured enzymatically using a mixture of cholesterol oxidase and peroxidase.

Determination of Liver HMG CoA-Reductase Activity (HMG COA)

Liver microsomes were prepared by homogenizing liver samples in phosphate / suscross buffer and then centrifuging. The final pellet material was resuspended in buffer and the amount was analyzed for HMG CoA reductase activity by incubation at 37 ° C. for 60 minutes in the presence of ¹⁴ C-HMG-CoA (Dupont-NEN). 6N HCl was added to stop the reaction, followed by centrifugation. A certain amount of the supernatant was separated by thin layer chromatography, the spot corresponding to the enzyme product was scraped from the plate, extracted, and the radioactivity was measured by scintillation counting. See Akerlund, J. and Bjorkhem, I. (1990) J. .Lipid Res. 31, 2159.

Determination of Serum Cholesterol (SER.CHOL, HDL-CHOL, TGI and VLDL + LDL)

Total serum cholesterol (SER.CHOL) was enzymatically measured using a commercial kit (Cholesterol C11, Cat. No. 276-64909) from Waco Pine Chemicals (Richmond, VA). HDL cholesterol (HDL-CHOL) was analyzed using the Waco kit after precipitating VLDL and LDL using the HDL cholester reagent, catalog number 352-3 (dextran sulfate method) from Sigma Chemical Company. Total serum triglycerides (blanked) (TGI) were analyzed enzymatically using Sigma Chemical Company GPO-Trinder, Cat. No. 337-B. VLDL and LDL (VLDL + LDL) cholesterol concentrations were calculated as the difference between total cholesterol and HDL cholesterol.

Determination of Liver Cholesterol 7-α-hydroxylase Activity (7a-OHase)

Liver microsomes were prepared by homogenizing liver samples in phosphate / suscross buffer and then centrifuging. The final pellet material was resuspended in buffer and the amount was analyzed for cholesterol 7-α-hydroxylase activity by incubation at 37 ° C. for 5 minutes in the presence of NADPH. After extraction with petroleum ether, the organic solvent is evaporated and the residue is dissolved in acetonitrile / methanol. The enzyme product was isolated by pouring a certain amount of extract on a C ₁₈ reversed phase HPLC column and quantifying the eluted material by UV detection (240 nm). See Horton, JD, et al. (1994) J. Clin. Invest. 93, 2084.

Rat gavage assay

Male Bicester rats (275-300 g) were administered an IBAT inhibitor using an oral gavage procedure. Drugs or excipients (0.2% Tween 80 in water) were administered once daily (between 9 am and 10 am) for 4 days with varying doses to a final volume of 2 ml per kg body weight. Total bowel samples were collected for 48 hours of total treatment period and the bile acid content was analyzed using the enzyme assay described above. Compound efficacy was measured by comparing the increase in fecal bile acid (FBA) concentration of treated rats with the average FBA concentration of rats belonging to the excipient treatment group.

Determination of Fecal Bile Acid Concentration (FBA)

The total defecation of each raised hamster was collected for 24 or 48 hours, dried under nitrogen, and then ground and weighed. About 0.1 g was weighed and extracted with organic solvent (butanol / water). After separation and drying, the residue was dissolved in methanol and the bile acid content was measured enzymatically via a 3α-hydroxysteroid steroid dehydrogenase reaction with bile acid reducing NAD. Mashige, F., et al. (1981) Clin. Chem. 27, 1352.

To the rabbit clamshell membrane (BBMV) ³ H] taurocholate absorption

Rabbit ileum membranes were prepared from the frozen ileum mucosa using the calcium precipitation method initiated by Malatti et al. [1979: Biochimica Biophysica Acta, 554, 259]. The method for measuring taurocholate is mostly described in Kramer et al. Except that 200 μl of the assay dose is used instead of 100 μl. (1992) Biochimica Biophysica Acta, 1111, 93. Briefly, 190 μl of a solution containing 2 μM [ ³ H] -tauurocholate (0.75 μCi), 20 mM Tris, 100 mM NaCl, 100 mM mannitol (pH 7.4) and 10 μl of a natural membrane vesicle (protein 60-120 μg) were added. Incubated at room temperature for 5 seconds. This incubation is initiated after the addition of BBMV with vortexing, immediately after addition of 5 ml of ice cold buffer (20 mM Hepes-tris, 150 mM KCl), filtered through a nylon filter (0.2 μm pore) and further addition to a stop buffer. Wash the ml to stop the reaction.

Acyl-CoA; Cholesterol Acyl Transferase (ACAT)

Hamster liver and rat intestinal microsomes were prepared from tissue as described above (J. Biol. Chem. 255, 9098) and used as ACAT enzyme sources. This assay included 2 mM DTT pH 7,4 buffer containing 200 μg microsomal protein and 0.25% BSA, 2.0 ml incubation solution containing 24 μM oleoyl-CoA (0.05 μCi) in 50 mM sodium phosphate. Assay initiation was initiated by the addition of oleoyl-CoA. The reaction was allowed to proceed for 5 minutes at 37 ° C. and terminated by adding 8.0 ml of chloroform / methanol (2: 1). To the extract, 125 µg of cholesterol oleate in chloroform methanol serving as a carrier was added, and the organic and aqueous phases of the extract were sufficiently vortexed and separated by centrifugation. The chloroform phase was dehydrated and then dropped onto a silica gel 60 TLC plate and developed with hexane / ethyl ether (9: 1). The amount of cholesterol ester formed was analyzed by measuring radioactivity contained in the cholesterol oleate drop on the TLC plate using a Packard instructor.

Rat gavage nutritional analysis data of some additional compounds described herein Example number of the compound Experiment number Dose (mg / kg / day) δ (fecal bile acid μM / day) 1402 28 5.2.04 58.21.30.3 1402 30 2.4.08.016 50.340.948.522.9 1403 30 2.4.08.016 50.340.948.522.9 1404 28 5.2.04 93.759.133.5 1406 32 2.4.08.016 47.831.612.8-8.5 1407 32 2.4.08.016 51.930.127.56.4 1407 33 2.4.08.016 3512.7-.04-4.5 1408 29 2.4.08.016 41.236.816.8-3.3 1408 37 2.4.08.016 26.245.226.36.6 1409 33 2.4.08.016 19.228.714.1-1.7 1409 41 2.4.08.016 44.235.914.511 1410 33 32.434.327.99.3 1410 35 2.4.08.016 26.236.518.520.4

Example number of the compound Experiment number Dose (mg / kg / day) δ (fecal bile acid μM / day) 1411 34 2.4.08.016 63.454.13322.3 1413 26 5.2.04 52.342.419 1414 27 5.2.04 45.239.514.3 1414 31 2.4.08.016 41.533.7293.8 1415 28 5.2.04 59.948.123.9 1415 37 2.4.08.016 48.925.727.112.7 1416 29 2.4.08.016 46.121.925-7.8 1417 31 2.4.08.016 51.44239.629.3 1418 29 2.4.08.016 20.329.5-4.6-10 1419 31 2.4.08.016 28.513.910.35.8 1420 31 2.4.08.016 53.14538.129.6 1421 32 2.4.08.016 57.827.725.34.7 1423 34 2.4.08.016 56.569.335.314.4

Example number of the compound Experiment number Dose (mg / kg / day) δ (fecal bile acid μM / day) 1425 21 5.2.04 91.8100.66.4 1425 30 2.4.08.016 44.66269.531.6 1425 40 2.4.08.016 48.34531.230 1426 33 2.4.08.016 52.419.523.124.6 1426 35 2.4.08.016 37.741.740.524.6 1426 39 2.4.08.016 54.348.751.826.8 1426 43 2.4.08.016 40.821.75.94.1 1427 40 2.4.08.016 36.735.827.313.8 1428 34 2.4.08.016 40.464.924.412.2 1428 42 2.4.08.016 4640.7261.1 1429 41 2.4.08.016 34.524.918.79.2 1429 42 2.4.08.016 47.131.135.54.8

Example number of the compound Experiment number Dose (mg / kg / day) δ (fecal bile acid μM / day) 1430 30 2.4.08.016 51.250.420.7-5.6 1431 32 28.345.821.91.1 1432 28 5.2.04 36.29.72.4 1433 24 202.2 66.547.426.5

The above examples can be repeated using reactants and / or operating conditions described generally or specifically in the present invention instead of those used in these examples.

Thus, it will be apparent that the invention described above may be modified in various ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and it is well known to those skilled in the art that all such modifications and equivalents are included within the scope of the following claims.

Claims (156)

A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof: [Formula I] In the above formula, q is an integer from 1 to 4; n is an integer from 0 to 2; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ⁺ R ⁹ May have one or more carbons replaced by A ⁻ , P ⁺ R ⁹ R ¹⁰ A ⁻ or phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above; R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² , Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring; R ⁵ is aryl substituted with one or more OR ^13a , Wherein R ^13a is in the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl Selected, R ^13a is hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, sphere No ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN , _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 A - , and C (O May be substituted with one or more groups selected from the group consisting of OM, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military, Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, 4 is a heterocycle, and 4-heteroaryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR 9, S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶ ) may be substituted with one or more substituents selected from the group consisting of OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a. The compound of claim 1, wherein R ⁵ is phenyl substituted with OR ^13a ; R ^13a is independently selected from the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl and carboxyalkylaminocarbonylalkyl; R ^13a may be substituted with one or more groups selected from the group consisting of carboxy, tetravalent heterocycle, tetravalent heteroaryl, and NR ⁹ R ¹⁰ . 2. Compounds of formula I according to claim 1, wherein n is 1 or 2. The compound of formula I according to claim 1, wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl. 2. Compounds of formula I according to claim 1, wherein R ⁷ and R ⁸ are hydrogen. The compound of formula I according to claim 1, wherein R ³ and R ⁴ are independently selected from the group consisting of hydrogen and OR ⁹ . The compound of formula I according to claim 1, wherein R ³ is hydrogen and R ⁴ is hydroxy. The compound of formula I according to claim 1, wherein at least one R ^x is independently selected from the group consisting of OR ¹³ and NR ¹³ R ¹⁴ . The compound of formula I according to claim 1, wherein at least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. The compound of formula I according to claim 1, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 1, wherein R ¹ and R ² are independently selected from the group consisting of alkyl. ^2. Compounds of formula I according to claim 1, wherein R ¹ and R ² are the same alkyl. ^2. Compounds of formula I according to claim 1, wherein R ¹ and R ² are each n-butyl. The compound of claim 1, wherein n is 1 or 2; R ¹ and R ² are n-butyl; R ³ and R ⁶ are hydrogen; R ⁴ is hydroxy; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. A compound of formula I according to claim 1 having the structure A compound of formula I according to claim 1 having the structure A compound of formula I according to claim 1 having the structure A compound of formula I according to claim 1 having the structure A compound of formula I according to claim 1 having the structure A compound of formula I according to claim 1 having the structure A compound selected from compounds having the structure: A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof: [Formula I] In the above formula, q is an integer from 1 to 4; n is an integer from 0 to 2; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ^{+ R 9 a -, P + R} 9 R 10 a - , or may have one or more carbon is replaced by a phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above; R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² , Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring; R ⁵ is aryl substituted with one or more OR ^13b , Wherein R ^13b is alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent Heterocycle, tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, R ^13b is substituted with one or more groups selected from the group consisting of carboxyalkyl, heterocycle, heteroaryl, heteroaryl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl or guanidinyl, R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military, Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Here, acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, tetravalent hetero heterocycle and 4 aryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ Or may be substituted with one or more substituents selected from the group consisting of PO (OR ¹⁶ ) OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a. The compound of claim 22, wherein R ⁵ is phenyl substituted with OR ^13b ; R ^13b is independently selected from the group consisting of alkyl, tetravalent heteroarylalkyl tetravalent heterocyclylalkyl; R ^13b may be substituted with one or more groups selected from the group consisting of heterocycle, heteroaryl and guanidinyl. 23. A compound of formula I according to claim 22, wherein n is 1 or 2. The compound of formula I according to claim 22, wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 22, wherein R ⁷ and R ⁸ are hydrogen. The compound of formula I according to claim 22, wherein R ³ and R ⁴ are independently selected from the group consisting of hydrogen and OR ⁹ . The compound of formula I according to claim 22, wherein R ³ is hydrogen and R ⁴ is hydroxy. The compound of formula I according to claim 22, wherein at least one R ^x is independently selected from the group consisting of OR ¹³ and NR ¹³ R ¹⁴ . The compound of formula I according to claim 22, wherein at least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. The compound of formula I according to claim 22, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 22, wherein R ¹ and R ² are independently selected from the group consisting of alkyl. The compound of formula I according to claim 22, wherein R ¹ and R ² are the same alkyl. The compound of formula I according to claim 22, wherein R ¹ and R ² are each n-butyl. The compound of claim 22, wherein n is 1 or 2; R ¹ and R ² are n-butyl; R ³ and R ⁶ are hydrogen; R ⁴ is hydroxy; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. The compound of formula I according to claim 22 having the formula: The compound of formula I according to claim 22 having the formula: A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof: [Formula I] In the above formula, q is an integer from 1 to 4; n is an integer from 0 to 2; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ^{+ R 9 a -, P + R} 9 R 10 a - , or may have one or more carbon is replaced by a phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above; R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² , Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring; R ⁵ is aryl substituted with one or more OR ^13b , Wherein R ^13b is alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent Heterocycle, tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkoxyalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, R ^13b is ^{OR 9a, NR 9a R 10,} N + R 9a R 11 R 12 A -, SR 9a, S (O) R 9a, SO 2 R 9a, SO 3 R 9a, CO 2 R 9a, CONR 9a R ¹⁰ , SO ₂ NR ^9a R ¹⁰ , P ⁺ R ^9a R ¹⁰ R ¹¹ A ^- and S ⁺ R ^9a R ¹⁰ A ^-and are substituted with one or more groups selected from the group consisting of Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, Wherein R ^9a is selected from the group consisting of carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxylalkylamino and carboxyalkylaminoalkyl; R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military, Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkoxyalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Here, acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, tetravalent hetero heterocycle and 4 aryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ May be substituted with one or more substituents selected from the group consisting of PO (OR ¹⁶ ) OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a. The compound of claim 38, wherein R ⁵ is phenyl substituted with OR ^13b ; R ^13b is independently selected from the group consisting of alkyl and alkoxyalkyl; R ^13b may be substituted with one or more groups selected from the group consisting of OR ^9a and NR ^9a R ¹⁰ ; R ^9a is selected from the group consisting of carboxyalkyl, carboxyheteroaryl and carboxyheterocycle; R ¹⁰ is carboxyalkyl. 39. A compound of formula I according to claim 38, wherein n is 1 or 2. The compound of formula I according to claim 38, wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 38, wherein R ⁷ and R ⁸ are hydrogen. The compound of formula I according to claim 38, wherein R ³ and R ⁴ are independently selected from the group consisting of hydrogen and OR ⁹ . The compound of formula I according to claim 38, wherein R ³ is hydrogen and R ⁴ is hydroxy. The compound of formula I according to claim 38, wherein at least one R ^x is independently selected from the group consisting of OR ¹³ and NR ¹³ R ¹⁴ . The compound of formula I according to claim 38, wherein at least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. The compound of formula I according to claim 38, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 38, wherein R ¹ and R ² are independently selected from the group consisting of alkyl. The compound of formula I according to claim 38, wherein R ¹ and R ² are the same alkyl. The compound of formula I according to claim 38, wherein R ¹ and R ² are each n-butyl. The compound of claim 38, wherein n is 1 or 2; R ¹ and R ² are n-butyl; R ³ and R ⁶ are hydrogen; R ⁴ is hydroxy; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. The compound of formula I according to claim 38, having the structure The compound of formula I according to claim 38, having the structure The compound of formula I according to claim 38, having the structure A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof: [Formula I] In the above formula, q is an integer from 1 to 4; n is an integer from 0 to 2; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ^{+ R 9 a -, P + R} 9 R 10 a - , or may have one or more carbon is replaced by a phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above; R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² , Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring; R ⁵ is aryl substituted with one or more OR ^13b , Wherein R ^13b is alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent Heterocycle, tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, R ^13b is carboxyalkyl ^{heterocyclyl, NR 9 R 10a, CONR 9} R 10a, SO 2 NR 9 R 10a, P + R 9 R 10a R 11 A - selected from the group consisting of ^- and S ⁺ R ⁹ R ^10a A Substituted with one or more groups, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, Wherein R ^10a is selected from the group consisting of carboxyalkyl, carboalkoxyalkyl, carboxylalkylamino, heteroarylalkyl and heterocyclylalkyl; R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military, Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Here, acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, tetravalent hetero heterocycle and 4 aryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ Or may be substituted with one or more substituents selected from the group consisting of PO (OR ¹⁶ ) OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a. The compound of claim 55, wherein R ⁵ is phenyl substituted with OR ^13b ; R ^13b is alkyl; R ^13b is substituted with carboxyalkylheterocyclylthio or NR ⁹ R ^10a ; R ⁹ is hydrogen; R ¹⁰ is heteroarylalkyl. The compound of formula I according to claim 55, wherein n is 1 or 2. The compound of formula I according to claim 55, wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 55, wherein R ⁷ and R ⁸ are hydrogen. The compound of formula I according to claim 55, wherein R ³ and R ⁴ are independently selected from the group consisting of hydrogen and OR ⁹ . The compound of formula I according to claim 55, wherein R ³ is hydrogen and R ⁴ is hydroxy. The compound of formula I according to claim 55, wherein at least one R ^x is independently selected from the group consisting of OR ¹³ and NR ¹³ R ¹⁴ . The compound of formula I according to claim 55, wherein at least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. The compound of formula I according to claim 55, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 55, wherein R ¹ and R ² are independently selected from the group consisting of alkyl. The compound of formula I according to claim 55, wherein R ¹ and R ² are the same alkyl. The compound of formula I according to claim 55, wherein R ¹ and R ² are each n-butyl. The compound of claim 55, wherein n is 1 or 2; R ¹ and R ² are n-butyl; R ³ and R ⁶ are hydrogen; R ⁴ is hydroxy; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. The compound of formula I according to claim 55 having the structure The compound of formula I according to claim 55 having the structure A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof: [Formula I] In the above formula, q is an integer from 1 to 4; n is an integer from 0 to 2; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ^{+ R 9 a -, P + R} 9 R 10 a - , or may have one or more carbon is replaced by a phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ and R ⁴ are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ is selected from wherein R ⁹ and R ¹⁰ are as defined above; R ³ and R ⁴ together form = O, = NOR ¹¹ , = S, = NNR ¹¹ R ¹² , = NR ⁹ or = CR ¹¹ R ¹² , Wherein R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl , OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ Where R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring; R ⁵ is NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ Aryl substituted with one or more substituents independently selected from the group consisting of NR ¹³ SO ₂ R ¹⁴ , NR ¹³ SONR ¹⁴ R ^15, and NR ¹³ SO ₂ NR ¹⁴ R ¹⁵ , Wherein R ¹³ , R ¹⁴ and R ¹⁵ are hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, Consisting of heterocycle, heteroaryl, tetravalent heterocycle, tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl Selected from the military, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ⁶ consists of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO ₃ R ⁹ Selected from the military, Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Here, acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, tetravalent hetero heterocycle and 4 aryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ May be substituted with one or more substituents selected from the group consisting of PO (OR ¹⁶ ) OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a. The compound of formula I according to claim 71, wherein R ⁵ is aryl substituted with a radical selected from the group consisting of NR ¹³ C (O) NR ¹⁴ R ¹⁵ and NR ¹³ CO ₂ R ¹⁴ . The compound of formula I according to claim 71, wherein R ⁵ is phenyl substituted with a radical selected from the group consisting of NR ¹³ C (O) NR ¹⁴ R ¹⁵ and NR ¹³ CO ₂ R ¹⁴ . 72. The compound of formula I according to claim 71, wherein n is 1 or 2. The compound of formula I according to claim 71, wherein R ⁷ and R ⁸ are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 71, wherein R ⁷ and R ⁸ are hydrogen. The compound of formula I according to claim 71, wherein R ³ and R ⁴ are independently selected from the group consisting of hydrogen and OR ⁹ . The compound of formula I according to claim 71, wherein R ³ is hydrogen and R ⁴ is hydroxy. The compound of formula I according to claim 71, wherein at least one R ^x is independently selected from the group consisting of OR ¹³ and NR ¹³ R ¹⁴ . The compound of formula I according to claim 71, wherein at least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. The compound of formula I according to claim 71, wherein R ¹ and R ² are independently selected from the group consisting of hydrogen and alkyl. The compound of formula I according to claim 71, wherein R ¹ and R ² are independently selected from the group consisting of alkyl. The compound of formula I according to claim 71, wherein R ¹ and R ² are the same alkyl. The compound of formula I according to claim 71, wherein R ¹ and R ² are each n-butyl. The compound of claim 71, wherein n is 1 or 2; R ¹ and R ² are n-butyl; R ³ and R ⁶ are hydrogen; R ⁴ is hydroxy; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently selected from the group consisting of methoxy and dimethylamino. 72. A compound of formula I according to claim 71 having the formula 72. A compound of formula I according to claim 71 having the formula A compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof: [Formula I] In the above formula, q is 1 or 2; n is 2; R ¹ and R ² are each alkyl; R ³ is hydroxy; R ⁴ and R ⁶ are hydrogen; R ⁵ is represented by Formula II: [Formula II] In the above formula, t is an integer from 0 to 5; At least one R ^y is OR ¹³ ; R ¹³ is hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, alkylarylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heteroarylalkyl and Selected from the group consisting of alkoxyalkyl; It said R ¹³ alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups are ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9 ^{, P + R 9 R 10 a} -, P (O) R 9, phenylene, carbohydrate, amino optionally having one or more carbon is replaced by a peptide or polypeptide, and; R ¹³ is a sulfoalkyl, tetravalent heterocyclic, 4 ^{heteroaryl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO ₃ R ^9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A - May be substituted with one or more groups selected from the group consisting of S ⁺ R ⁹ R ¹⁰ A ^- and C (O) OM, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, R ⁹ and R ¹⁰ are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl and alkylammoniumalkyl; R ¹¹ and R ¹² are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR ⁹ , NR ⁹ R ¹⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , CO ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , wherein R ⁹ and R ¹⁰ are as defined above, provided that R ³ and R ⁴ are not both OH, NH ₂ and SH, or R ¹¹ and R ¹² together with the carbon atom or nitrogen to which they are attached form a cyclic ring; R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently selected from the group consisting of alkoxy, alkylamino and dialkylamino. 89. The compound of formula I according to claim 88, wherein R ¹ and R ² are each n-butyl. 91. The compound of formula I according to claim 89, wherein t is 1, R ^y is OR ¹³ and R ¹³ is as defined in claim 88. 91. The compound of formula I according to claim 90, wherein at least one R ^x is independently selected from methoxy and dimethylamino. 91. The compound of formula I according to claim 90, wherein R ^x is dimethylamino. 91. The compound of formula I according to claim 90, wherein t is 1, R ^y is para-OR ¹³ and R ¹³ is as defined in claim 88. 91. The compound of formula I according to claim 90, wherein t is 1, R ^y is meta-OR ¹³ and R ¹³ is as defined in claim 88. 91. The compound of formula I according to claim 90, having the 4R, 5R form. 96. A pharmaceutical composition comprising an amount effective to prevent hyperlipidemic conditions of a compound of any one of claims 1 to 95 and a pharmaceutically acceptable carrier. 96. A pharmaceutical composition comprising an amount effective for preventing atherosclerosis of the compound of any one of claims 1 to 95 and a pharmaceutically acceptable carrier. 96. A pharmaceutical composition comprising an amount effective to prevent hypercholesterolemia of a compound of any one of claims 1 to 95 and a pharmaceutically acceptable carrier. 97. A method of preventing or treating a hyperlipidemic condition comprising administering the composition of claim 96 to a patient in need thereof in unit dosage form. 97. A method of preventing or treating an atherosclerosis condition comprising administering the composition of claim 97 to a patient in need thereof in unit dosage form. 99. A method for preventing or treating hypercholesterolemia, comprising administering the composition of claim 98 to a patient in need thereof in unit dosage form. Use of the compound of any one of claims 1 to 95 for the manufacture of a medicament for the prevention or treatment of hyperlipidemic conditions. Use of the compound of any one of claims 1 to 95 for the manufacture of a medicament for the prevention or treatment of atherosclerosis conditions. Use of the compound of any one of claims 1 to 95 for the manufacture of a medicament for the prevention or treatment of a hypercholesterolemia state. Treating thiophenol with an extractant; Coupling thiophenyl and cyclic sulfate to form an intermediate comprising a sulfate group; And forming a compound of formula (XLI) in which the sulfate group of the intermediate is formed: [Formula XLI} In the above formula, q is an integer from 1 to 4; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ⁺ R ⁹ May have one or more carbons replaced by A ⁻ , P ⁺ R ⁹ R ¹⁰ A ⁻ or phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ is hydroxy; R ⁴ is hydrogen; R ⁵ and R ⁶ are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO Selected from the group consisting of ₃ R ⁹ , Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, 4 is a heterocycle, and 4-heteroaryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR 9, S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶ ) may be substituted with one or more substituents selected from the group consisting of OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a. 107. The process of claim 105, wherein the cyclic sulfate is represented by formula XL and the thiophenol is represented by formula XVIIIA: [Formula XL] [Formula XVIIIA] In the formulas above, R ¹ , R ² , R ⁵ , R ^X and q are as defined in claim 105. 107. The method of claim 105, wherein the sulfate group is removed by treating the intermediate with a hydrolytic agent. 107. The method of claim 107, wherein the hydrolysing agent is a mineral acid. 107. The process of claim 107, wherein the hydrolyzing agent is selected from hydrochloric acid and sulfuric acid. 107. The method of claim 106, wherein the extractant is a base having a pH of about 10 or greater. 107. The method of claim 106, wherein the extractant is an alkali metal hydride. 107. The method of claim 106, wherein the extractant is sodium hydride. 107. The method of claim 106, wherein R ¹ and R ² are independently selected from alkyl. 107. The process of claim 106, wherein R ¹ and R ² are independently selected from the group consisting of ethyl, n-butyl, isobutyl and pentyl. 107. The method of claim 106, wherein R ¹ and R ² are n-butyl. Reacting the cyclic sulfate with thiophenol to form an alcohol; Oxidizing the alcohol to produce sulfone-aldehyde; And cyclizing the sulfone-aldehyde to form a compound of formula I: [Formula I] In the above formula, q is an integer from 1 to 4; n is 2; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ⁺ R ⁹ May have one or more carbons replaced by A ⁻ , P ⁺ R ⁹ R ¹⁰ A ⁻ or phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ is hydroxy; R ⁴ is hydrogen; R ⁵ and R ⁶ are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO Selected from the group consisting of ₃ R ⁹ , Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, n + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, 4 is a heterocycle, and 4-heteroaryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR 9, S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶ ) may be substituted with one or more substituents selected from the group consisting of OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a. 116. The process of claim 116, wherein the cyclic sulfate is represented by formula XL and thiophenol is represented by formula XVIIIA: [Formula XL] [Formula XVIIIA] In the formulas above, R ¹ , R ² , R ⁵ , R ^X and q are as defined in claim 116. 118. The process of claim 117, wherein R ¹ and R ² are independently selected from alkyl. 118. The process of claim 117, wherein R ¹ and R ² are independently selected from the group consisting of ethyl, n-butyl, isobutyl and pentyl. 118. The process of claim 117, wherein R ¹ and R ² are n-butyl. 118. The method of claim 117, wherein the alcohol is oxidized with an oxidant to form an aldehyde. 121. The method of claim 121, wherein the compound is oxidized with an aldehyde oxidant to form sulfone-aldehyde. 118. The method of claim 117, wherein the sulfone-aldehyde is cyclized with a cyclizing agent that is a base at a pH of about 8 to about 9. 118. The method of claim 117, wherein the sulfone-aldehyde is cyclized with a cyclizing agent that is an alkali alkoxide base. 118. The process of claim 117, wherein the sulfone-aldehyde is cyclized with potassium tertiary butoxide. 118. The method of claim 117, wherein the alcohol is oxidized with pyridinium chlorochromate to form aldehydes; Aldehydes are oxidized with metachloroperbenzoic acid to form sulfone-aldehydes; A method for preparing a compound, wherein the sulfone-aldehyde is cyclized to potassium tertiary butoxide. Treating halobenzene with an extractant; Coupling the halobenzenes and the cyclic sulfate to form an intermediate comprising sulfate groups; And forming a compound of formula LI, wherein the sulfate group of the intermediate is formed: [Formula LI] In the above formula, q is an integer from 1 to 4; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ⁺ R ⁹ May have one or more carbons replaced by A ⁻ , P ⁺ R ⁹ R ¹⁰ A ⁻ or phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ is hydroxy; R ⁴ is hydrogen; R ⁵ and R ⁶ are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO Selected from the group consisting of ₃ R ⁹ , Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, 4 is a heterocycle, and 4-heteroaryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR 9, S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶ ) may be substituted with one or more substituents selected from the group consisting of OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a; R ^e is an electron attraction group located at the para or ortho position. 127. The process of claim 127, wherein the cyclic sulfate is represented by formula XL and halobenzene is represented by formula L: [Formula XL] [Formula L] In the formulas above, R ^h is halogen and R ¹ , R ² , R ⁵ , R ^X , R ^e and q are as defined in claim 127. 129. The method of claim 128, wherein the sulfate group is removed by treating the intermediate with a hydrolytic agent. 129. The method of claim 129, wherein the hydrolysing agent is a mineral acid. 129. The process of claim 129, wherein the hydrolyzing agent is selected from hydrochloric acid and sulfuric acid. 129. The method of claim 128, wherein the extractant is dialkali metal sulfide. 129. The method of claim 128, wherein the extractant is dilithium sulfide. 129. The process of claim 128, wherein R ¹ and R ² are independently selected from alkyl. 129. The process of claim 128, wherein R ¹ and R ² are independently selected from the group consisting of ethyl, n-butyl, isobutyl and pentyl. 129. The method of claim 128, wherein R ¹ and R ² are n-butyl. 129. The process of claim 128, wherein R ^h is chloro. 129. The method of claim 128, wherein R ^e is p-nitro. Reacting the cyclic sulfate with halobenzene to form an alcohol; Oxidizing the alcohol to produce sulfone-aldehyde; And cyclizing the sulfone-aldehyde to form a compound of formula (I): [Formula I] In the above formula, q is an integer from 1 to 4; n is 2; R ¹ and R ² are independently a group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl Is selected from Wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl) aryl and cycloalkyl are OR ⁹ , NR ⁹ R ¹⁰ , N ^{+ R 9 R 10 R w A -} , SR 9, S * R 9 R 10 A -, P + R 9 R 10 R 11 A -, S (O) R 9, SO 2 R 9, SO 3 R 9, CO _May be substituted with one or more substituents selected from the group consisting of ₂ R ⁹ , CN, halogen, oxo and CONR ⁹ R ¹⁰ , Alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl) aryl, and cycloalkyl is O, NR ^9, N ⁺ R ⁹ R ¹⁰ A ^-, S, SO, SO _2, S ⁺ R ⁹ May have one or more carbons replaced by A ⁻ , P ⁺ R ⁹ R ¹⁰ A ⁻ or phenylene, R ⁹ , R ¹⁰ and R ^w are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carbo Alkoxyalkyl, carboxyalkylamino, carboxyalkylaminoalkyl, heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; or R ¹ and R ² together with the carbon atom to which they are attached form C ₃ -C ₁₀ cycloalkyl; R ³ is hydroxy; R ⁴ is hydrogen; R ⁵ and R ⁶ are independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle, OR ³⁰ , SR ⁹ , S (O) R ⁹ , SO ₂ R ⁹ and SO Selected from the group consisting of ₃ R ⁹ , Wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, Heterocycle, arylalkyl, tetravalent heterocycle, tetravalent heteroaryl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , C (O) NR ¹³ R ¹⁴ , C (O) OM, COR ¹³ , NR ¹³ C (O) R ¹⁴ , NR ¹³ C (O) NR ¹⁴ R ¹⁵ , NR ¹³ CO ₂ R ¹⁴ , OC (O) R ¹³ , OC (O) NR ¹³ R ¹⁴ , NR ¹³ SOR ¹⁴ , NR _{^{13 SO 2 R 14, NR 13}} SONR 14 R 15, NR 13 SO 2 NR 14 R 15, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 14, S ⁺ R ¹³ R ¹⁴ a ^-, and ^{N + R 9 R 11 R 12} a - in which may be substituted by one or more substituents independently selected from the group consisting of, Wherein A ⁻ is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl and heterocycle are OR ⁷ , NR ⁷ R ⁸ , SR ⁷ , S (O) R ⁷ , SO ₂ R ⁷ , SO is, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, _{^{arylalkyl, 4 - 3 R 7, CO}} 2 R 7, CN, ^{oxo, CONR 7 R 8, N +} R 7 R 8 R 9 a Heterocycle, tetravalent heteroaryl, P (O) R ⁷ R ⁸ , P ⁺ R ⁷ R ⁸ R ⁹ A ^- and P (O) (OR ⁷ ) OR ⁸ further substituted with one or more substituents selected from the group consisting of Can be, Wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocyclyl is O, NR ^7, N ⁺ R ⁷ R ⁸ A ^-, S, SO, SO _2, S ^{+ R 7 a -, PR 7} , P (O) R 7, P + R 7 R 8 a - , or may have one or more carbon is replaced by a phenylene, R ^13, R ¹⁴ and R ¹⁵ are independently Hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, tetravalent heterocycle, Tetravalent heteroaryl, heterocyclylalkyl, heteroarylalkyl, tetravalent heterocyclylalkyl, tetravalent heteroarylalkyl, alkylammoniumalkyl and carboxyalkylaminocarbonylalkyl, Wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, ^{P + R 9 R 10 a -} , P (O) R 9, phenylene, carbohydrate, amino acid, and optionally having one or more carbon is replaced by a peptide or polypeptide, R ¹³ , R ¹⁴ and R ¹⁵ are hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, tetravalent heterocycle, tetravalent heteroaryl, tetravalent heterocyclylalkyl, 4 is heteroarylalkyl, guanidyl ^{pyridinyl, OR 9, NR 9 R 10} , N + R 9 R 11 R 12 a -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, _{^{halogen, CONR 9 R 10, SO 2}} OM, SO 2 NR 9 R 10, PO (OR 16) OR 17, P + R 9 R 10 R 11 A -, S + R 9 R 10 May be substituted with one or more groups selected from the group consisting of A ⁻ and C (O) OM, Wherein R ¹⁶ and R ¹⁷ are independently selected from substituents constituting R ⁹ and M; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle which may be substituted with one or more radicals selected from the group consisting of oxo, carboxy and tetravalent salts; or R ¹⁴ and R ¹⁵ together with the nitrogen atom to which they are attached form a cyclic ring; R ³⁰ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, arylalkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino , Heteroarylalkyl, heterocyclylalkyl and alkylammoniumalkyl; R ⁷ and R ⁸ are hydrogen; At least one R ^x is independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, tetravalent heterocycle, 4 is ^{heteroaryl, OR 13, NR 13 R 14} , SR 13, S (O) R 13, S (O) 2 R 13, SO 3 R 13, S + R 13 R 14 a -, NR 13 OR 14, NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ NR ¹³ R ¹⁴ , NR ¹⁴ C (O) R ¹³ , C (O) NR ¹³ R ¹⁴ , NR ^{14 C (O) R 13, C} (O) OM, COR 13, OR 18, S (O) n NR 18, NR 13 R 18, NR 18 OR 14, N + R 9 R 11 R 12 A -, P + ^{R 9 R 11 R 12 a -} , amino acid, are selected from the group consisting of a peptide, polypeptide, and carbohydrate, Wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, tetravalent heterocycle and tetravalent heteroaryl are OR ⁹ , NR ⁹ R ^{10 , N + R 9 R 11 R} 12 A -, SR 9, S (O) R 9, SO 2 R 9, SO 3 R 9, oxo, CO ₂ R ^9, CN, halogen, CONR ⁹ R ^10, SO _{2 ^{OM, SO 2 NR 9 R 10}} , PO (oR 16) oR 17, P + R 9 R 11 R 12 a - , and may be further substituted or ^{C (O) OM, -,} S + R 9 R 10 a Wherein R ¹⁸ is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, Acyl, aryl, alkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, 4 is a heterocycle, and 4-heteroaryl is ^{OR 9, NR 9 R 10,} N + R 9 R 11 R 12 A -, SR 9, S (O) R ⁹ , SO ₂ R ⁹ , SO ₃ R ⁹ , oxo, CO ₂ R ⁹ , CN, halogen, CONR ⁹ R ¹⁰ , SO ₃ R ⁹ , SO ₂ OM, SO ₂ NR ⁹ R ¹⁰ , PO (OR ¹⁶ ) may be substituted with one or more substituents selected from the group consisting of OR ¹⁷ and C (O) OM, Wherein at least one carbon of R ^x is O, NR ¹³ , N ⁺ R ¹³ R ¹⁴ A ⁻ , S, SO, SO ₂ , S ⁺ R ¹³ A ⁻ , PR ¹³ , P (O) R ¹³ , P ⁺ R ¹³ R ¹⁴ a ^-, phenylene, may be replaced by an amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl, Said polyalkyl, phenylene, amino acid, at least one carbon in the peptide, polypeptide, and carbohydrate is ^{O, NR 9, N + R} 9 R 10 A -, S, SO, SO 2, S + R 9 A -, PR 9, May be replaced by P ⁺ R ⁹ R ¹⁰ A ^- or P (O) R ⁹ ; The tetravalent heterocycle and tetravalent heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR ¹³ , NR ¹³ R ¹⁴ , SR ¹³ , S (O) R ¹³ , SO ₂ R ¹³ , SO ₃ R ¹³ , NR ¹³ OR ¹⁴ , NR ¹³ NR ¹⁴ R ¹⁵ , NO ₂ , CO ₂ R ¹³ , CN, OM, SO ₂ OM, SO ₂ ^{NR 13 R 14, C (O} ) NR 13 R 14, C (O) OM, COR 13, P (O) R 13 R 14, P + R 13 R 14 R 15 A -, P (OR 13) OR 4 ^{, S + R 13 R 14 a} - may be substituted with one or more groups selected from the group consisting of ^- and ^{N + R 9 R 11 R 12} a; R ^e is an electron withdrawing group located at the para or ortho position. 141. The process of claim 139, wherein the cyclic sulfate is represented by formula XL and thiophenol is represented by formula L: [Formula XL] [Formula L] In the formulas above, R ¹ , R ² , R ⁵ , R ^X and R ^e are as defined in claim 139 and R ^h is halogen. 141. The method of claim 140, wherein the sulfate group is removed by treating the intermediate with a hydrolytic agent. 145. The method of claim 141, wherein the hydrolyzating agent is a mineral acid. 141. The process of claim 140, wherein the hydrolyzing agent is selected from hydrochloric acid and sulfuric acid. 141. The method of claim 140, wherein the extractant is dialkali metal sulfide. 141. The method of claim 140, wherein the extractant is dilithium sulfide. 141. The method of claim 140, wherein R ¹ and R ² are independently selected from alkyl. 141. The process of claim 140, wherein R ¹ and R ² are independently selected from the group consisting of ethyl, n-butyl, isobutyl and pentyl. 141. The method of claim 140, wherein R ¹ and R ² are n-butyl. 141. The method of claim 140, wherein R ^h is chloro. 141. The method of claim 140, wherein R ^e is p-nitro. 141. The method of claim 140, wherein the alcohol is oxidized with an oxidant to form sulfone. 141. The method of claim 140, wherein the sulfone is oxidized with an oxidant to form sulfone-aldehyde. 141. The method of claim 140, wherein the sulfone-aldehyde is cyclized with a cyclizing agent that is a base at a pH of about 8 to about 9. 141. The process of claim 140, wherein the sulfone-aldehyde is cyclized with a cyclizing agent that is an alkali alkoxide base. 141. The process of claim 140, wherein the sulfone-aldehyde is cyclized with potassium tertiary butoxide. 143. The method of claim 140, wherein the alcohol is oxidized with metachloroperbenzoic acid to form sulfones; Aldehydes are oxidized with pyridinium chlorochromate to form sulfone-aldehydes; A method for preparing a compound, wherein the sulfone-aldehyde is cyclized to potassium tertiary butoxide.